EP4247386A1 - Formulations de flumazénil pour injection sous-cutanée et méthodes de traitement utilisant des modulateurs du récepteur gaba - Google Patents

Formulations de flumazénil pour injection sous-cutanée et méthodes de traitement utilisant des modulateurs du récepteur gaba

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Publication number
EP4247386A1
EP4247386A1 EP21895529.2A EP21895529A EP4247386A1 EP 4247386 A1 EP4247386 A1 EP 4247386A1 EP 21895529 A EP21895529 A EP 21895529A EP 4247386 A1 EP4247386 A1 EP 4247386A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
flumazenil
disorder
withdrawal
pharmaceutical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21895529.2A
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German (de)
English (en)
Inventor
Jeffrey Becker
Gregg Peterson
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Bexson Biomedical Inc
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Bexson Biomedical Inc
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Filing date
Publication date
Application filed by Bexson Biomedical Inc filed Critical Bexson Biomedical Inc
Publication of EP4247386A1 publication Critical patent/EP4247386A1/fr
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Benzodiazepines represent one of most prescribed medication groups, particularly in primary care settings. This frequently results in benzodiazepine dependence in the subjects, treatment of which is often protracted tapering of the benzodiazepine over several weeks or months. This is often associated with significant withdrawal symptoms which can result in patient drop out and return to use. There exists a need for enhanced treatments and therapy regimens to deal with this problem.
  • Flumazenil is a selective gamma-aminobutyric acid (GABA) receptor antagonist that is specific for that GAB A A receptor. Flumazenil’ s action on this receptor makes it a potentially powerful tool for dealing with symptoms associated with acute and post-acute benzodiazepine withdrawal.
  • GABA gamma-aminobutyric acid
  • Flumazenil is readily metabolized by the liver, with less than 25% systemic availability after first pass hepatic metabolism. Subcutaneous delivery of flumazenil would thus be desirable, as it could be slowly administered to a patient over time to maintain a near constant concentration of flumazenil in the relevant tissues.
  • flumazenil s poor solubility ( ⁇ 0.1 mg/mL in USP flumazenil preparations) renders it difficult to formulate at a concentration that would be compatible with such use, which would require a high concentration of the drug in a small volume because validated therapies require daily administration of the drug at an amount of at least 2 mg/day. This would thus require a reservoir of approximately 20 mL for a single day of treatment, which is not compatible with realistic medical product expectations surrounding cost considerations, medical waste, patient usability and patient comfort in a 30 day wearable infusion device protocol.
  • the formulations of flumazenil provided herein have elevated concentrations of flumazenil, thus enabling continuous or near continuous administration of flumazenil over a long period of time from a single, small volume reservoir containing device.
  • GABA receptor modulators for treatment of a variety of other conditions, including alcohol dependence, sedative dependence, panic disorders, generalized anxiety disorders, post-traumatic stress disorders, mood disorders, major depression, dysthymia, chronic suicidality, anxiety disorder NOS, obsessive compulsive disorder, eating disorder NOS, anorexia nervosa, bulimia nervosa, intermittent explosive disorder, a sleep disorder, insomnia NOS, a pain disorder, a chronic pain disorder, idiopathic hypersomnia, and narcolepsy.
  • a pharmaceutical composition comprising: (i) flumazenil, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a form for dosing or administration by subcutaneous injection; and wherein the concentration of flumazenil in the pharmaceutical composition is greater than 0.7 mg/mL.
  • the at least one pharmaceutically acceptable excipient comprises a complexing agent.
  • the complexing agent is a substituted or unsubstituted cyclodextrin.
  • the complexing agent is a cyclodextrin substituted with at least one acidic functional group.
  • the complexing agent is a sulfobutyl-ether-beta-cyclodextrin (SBEBCD).
  • the complexing agent acts as a counterion to at least a portion of the flumazenil, wherein the portion of the flumazenil is protonated.
  • the complexing agent is a cyclodextrin substituted with at least one polar functional group.
  • the complexing agent is a hydroxypropyl -beta-cyclodextrin (HPBCD).
  • the molar ratio of complexing agent to flumazenil is from about 1 :10 to about 10: 1.
  • the pharmaceutical composition further comprises a base, a buffer, or a combination thereof.
  • the pharmaceutical composition further comprises an emulsifying agent, a surfactant, a solubilizing agent, a co-solvent or a combination thereof.
  • the co-solvent is ethanol, propylene glycol, tween 20, tween 80, or glycerin.
  • the pharmaceutical composition has a pH > about 4.
  • the pharmaceutical composition has a pH of about 4 to about 7.
  • the pharmaceutical composition has a pH of about 5 to about 8.
  • the concentration of flumazenil in the pharmaceutical composition is at least about 1 mg/mL. In some embodiments, the concentration of flumazenil in the pharmaceutical composition is at least about 5 mg/mL. In some embodiments, the concentration of flumazenil in the pharmaceutical composition is at most about 10 mg/mL. In some embodiments, the pharmaceutical composition further comprises a preservative. In some embodiments, the pharmaceutical composition has an osmolality of from about 300 mOsm/kgto about 500 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolality of less than about 500 mOsm/kg. In some embodiments, the pharmaceutical composition is adapted to be delivered to a subject over a period of at least two days.
  • the pharmaceutical composition is adapted to deliver a daily dose of at least 1 mg of flumazenil. In some embodiments, the pharmaceutical composition is adapted to be delivered by a wearable device. In some embodiments, the wearable device has a reservoir of the pharmaceutical composition of less than 10 mL.
  • a method of treating benzodiazepine dependence, withdrawal, or toxicity in a subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein.
  • the benzodiazepine withdrawal is acute withdrawal or post-acute withdrawal.
  • [006] in another aspect is a method of treating alcohol dependence, withdrawal, or toxicity, sedative dependence, withdrawal, or toxicity, hypnotic, withdrawal, dependence or toxicity, anxiolytic dependence, withdrawal, or toxicity, panic disorder, generalized anxiety disorder, post-traumatic stress disorder (PTSD), idiopathic hypersomnia, narcolepsy, a mood disorders, major depression, dysthymia, chronic suicidality, anxiety disorder NOS, obsessive compulsive disorder, eating disorder NOS, anorexia nervosa, bulimia nervosa, intermittent explosive disorder, a sleep disorder, insomnia NOS, a pain disorder, or a chronic pain disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of flumazenil, wherein the flumazenil is administered by subcutaneous injection in an amount of atleast 0.5 mg/day from a single device for a period of time of at least 2 days, wherein the single device has a reservoir volume less than 30 mL.
  • the disease or disorder is benzodiazepine dependence, withdrawal, or toxicity, alcohol dependence, withdrawal, or toxicity, sedative dependence, withdrawal, or toxicity, hypnotic dependence, withdrawal, or toxicity, anxiolytic dependence, withdrawal, or toxicity, panic disorder, generalized anxiety disorder, post-traumatic stress disorder (PTSD), idiopathic hypersomnia, narcolepsy, a mood disorder, major depression, dysthymia, chronic suicidality, anxiety disorder NOS, obsessive compulsive disorder, eating disorder NOS, anorexia nervosa, bulimia nervosa, intermittent explosive disorder, a sleep disorder, insomnia NOS, a pain disorders, or a chronic pain disorder .
  • PTSD post-traumatic stress disorder
  • idiopathic hypersomnia narcolepsy
  • a mood disorder major depression, dysthymia, chronic suicidality
  • anxiety disorder NOS obsessive compulsive disorder
  • eating disorder NOS
  • the disease or disorder is benzodiazepine dependence, withdrawal, or toxicity.
  • the benzodiazepine withdrawal is acute withdrawal or post-acute withdrawal.
  • the flumazenil is administered as a pharmaceutical composition having a concentration of flumazenil of greater than 0.7 mg/mL.
  • the flumazenil is administered in an amount of at least 0.5 mg/day, at least 1.0 mg/day, at least 1.5 mg/day, at least 2 mg/day, at least 3 mg/day, at least 4 mg/day, at least 5 mg/day, at least 7.5 mg/day, or at least 10 mg/day.
  • the method further comprises administering to the subject a therapeutically effective amount of flumazenil from one or more additional single devices, wherein each additional single device is administered to the subject after another iteration of the period of time.
  • the total time of administration is at least 10 days, at least 15 days, at least 20 days, at least 25 days, or at least 30 days.
  • the reservoir volume is less than 10 mL. In some embodiments, the reservoir volume is less than 5 mL.
  • the flumazenil is administered continuously.
  • the flumazenil is administered at a rate of at least about 40 pg/hr, at least about 60 pg/hr, at least about 80 pg/hr, at least about 100 pg/hr, at least about 150 pg/hr, at least about 200 pg/hr, or at least about 250 pg/hr.
  • a pharmaceutical composition comprising: (i) a pharmaceutical compound, wherein the pharmaceutical compound is a GAB A A receptor antagonist or modulator, a GABA receptor agonist, a GABA receptor partial agonist, a GABA A receptor negative allosteric modulator or inverse agonist, or salvinorin A, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient comprises a cyclodextrin substituted with at least one acidic functional group or a conjugate base thereof or a cyclodextrin substituted with at least one polar functional group, wherein the pharmaceutical composition is in a form for dosing or administration by subcutaneous injection.
  • the pharmaceutical compound is a GABA A receptor antagonist or modulator. In some embodiments, the pharmaceutical compound is flumazenil or pentylenetetrazol. In some embodiments, the pharmaceutical compound is a GABA receptor agonist. In some embodiments, the pharmaceutical compound is muscimol, thiomuscimol, or gaboxadol. In some embodiments, the pharmaceutical compound is a GABA receptor partial agonist.
  • the pharmaceutical compound is bretazenil, imidazenil, FG 8205 (7-chloro-5-methyl-3-(5-propan-2-yl-l,2,4-oxadiazol-3-yl)-4H- imidazo[l,5-a][l,4]benzodiazepin-6-one), abecamil, NS 2710 (l -[l-[3-(3- pyridyl)phenyl]benzimidazol-5-yl]ethanone O-ethyloxime), RWJ-51204 (5-ethoxymethyl-7- fluoro-3-oxo-l,2,3,5-tetrahydrobenzo[4,5] imidazo[l,2a]pyridine-4-N-(2- fluorophenyljcarboxamide), or premazepam.
  • the pharmaceutical compound is a GABA A receptor negative allosteric modulator or inverse agonist.
  • the pharmaceutical compound is bemegride, flurothyl, or pentylenetetrazol.
  • the pharmaceutical compound is an a5 subunit containing GAB A A receptor selective compound.
  • the pharmaceutical compound is basmisanil, a5IA (3-(5-methylisoxazol-3-yl)-6-[(l-methyl-lH-l,2,3-triazol-4-yl)methoxy][l,2,4]triazolo[3,4- a]phthalazine), L-655,708, MRK-016, PWZ-029, a Pyridazine, Ro4938581, TB-21007, FG- 7142 (N-Methyl-9H-pyrido[5,4-b]indole-3 -carboxamide), Rol6-0154 (ethyl 7-iodanyl-5- methyl-6-oxo-4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxylate), Radequinil, Ro 15-4513 (Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-
  • the pharmaceutical compound is salvinorin A.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of pharmaceutical compounds, wherein the pharmaceutical compound is a GABA A receptor antagonist or modulator, a GABA receptor agonist, a GABA receptor partial agonist, a GABAA receptor negative allosteric modulator or inverse agonist, or salvinorin A, wherein the pharmaceutical compound is administered by subcutaneous injection from a single device for a period of time of at least 2 days, wherein the single device has a reservoir volume less than 30 mL.
  • the disease or disorder is benzodiazepine dependence, withdrawal, or toxicity, alcohol dependence, withdrawal, or toxicity, sedative dependence, withdrawal, or toxicity, hypnotic dependence, withdrawal, or toxicity, anxiolytic dependence, withdrawal, or toxicity, panic disorder, generalized anxiety disorder, post -traumatic stress disorder (PTSD), idiopathic hypersomnia, narcolepsy, a mood disorder, major depression, dysthymia, chronic suicidality, anxiety disorderNOS, obsessive compulsive disorder, eating disorder NOS, anorexia nervosa, bulimia nervosa, intermittent explosive disorder, a sleep disorder, insomnia NOS, a pain disorder, or a chronic pain disorder.
  • the benzodiazepine withdrawal is acute withdrawal or post-acute withdrawal.
  • FIG. 1 shows a phase solubility curve with captisol and flumazenil.
  • compositions comprising flumazenil with reduced irritant effect to subcutaneous tissues and/or dermal tissues.
  • the compositions comprising flumazenil are formulated for subcutaneous administration.
  • the compositions are formulated to be administered to a subject over a period of at least two days, preferably from a wearable device.
  • methods of treating or preventing benzodiazepine dependence, withdrawal, and/or toxicity, and other disease and disorders with flumazenil and other GABA receptor modulators are also provided herein.
  • mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, and goats.
  • Non-mammals include, for example, fish and birds.
  • the terms “disease,” “disorder,” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein .
  • the disease may be a disease of dependence or withdrawal, such as benzodiazepine dependence or withdrawal, as well as toxicity.
  • the disease may be a mood disorder.
  • mental or psychiatric disorder refers to human mental or psychiatric disorders including major depressive disorder, treatment resistant major depressive disorder, dysthymia, Suicidality, Suicidal Ideation, bipolar I disorder, bipolar II disorder, post -traumatic stress disorder (PTSD), a substance-related disorder (e.g., cannabis dependence or withdrawal, barbiturate dependence or withdrawal, benzodiazepine dependence or withdrawal, amphetamine dependence or withdrawal, opioid dependence or withdrawal, alcohol dependence or withdrawal, or cocaine dependence or withdrawal.
  • major depressive disorder e.g., treatment resistant major depressive disorder, dysthymia, Suicidality, Suicidal Ideation, bipolar I disorder, bipolar II disorder, post -traumatic stress disorder (PTSD), a substance-related disorder (e.g., cannabis dependence or withdrawal, barbiturate dependence or withdrawal, benzodiazepine dependence or withdrawal, amphetamine dependence or withdrawal, opioid dependence or withdrawal, alcohol dependence or withdrawal, or cocaine dependence or withdrawal.
  • substance-related disorder
  • the expression “effective amount,” when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound (e.g. flumazenil) described herein that is effective to act on or modulate (e.g. inhibit) GABA receptors, such as the GABA A receptor, in the individual’s tissues wherein, wherein such modulating or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
  • a compound e.g. flumazenil
  • GABA receptors such as the GABA A receptor
  • “Substantially” as the term is used herein means completely or almost completely.
  • a composition that is “substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount.
  • a compound that is “substantially pure” has only negligible traces of impurities present.
  • an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an “isotopically labeled form” of the molecule.
  • All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated.
  • any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, e.g., protium ( X H), deuterium ( 2 H), or tritium ( 3 H) in any combination.
  • any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as n C, 12 C, 13 C, or 14 C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13 N, 14 N, or 15 N.
  • a molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi -molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition.
  • a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14 C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom . It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14 N and 15 N, 32 S and 34 S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule.
  • the isotopes can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry .
  • the isotopic forms are incorporated into precursors as required for use in any particular synthetic route .
  • 14 C and 3 H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14 C and 3 H are incorporated into precursor molecules, followed by further elaboration as needed.
  • a “hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a “hydrate” refers to a solid form, e.g., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is a similar composition except that a solvent other that water replaces the water.
  • a solvent other that water replaces the water.
  • methanol or ethanol can form an “alcoholate”, which can again be stoichiometic or non-stoichiometric.
  • a “solvate” refers to a solid form, e.g., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
  • a “prodrug” as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patient’s body, such as enzymes, to the active pharmaceutical ingredient.
  • prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Further examples of prodrugs include boronate esters which can be hydrolyzed under physiological conditions to afford the corresponding boronic acid. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed . H. Bundgaard, Elsevier, 1985.
  • Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
  • the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called “enantiomers.”
  • Single enantiomers of a pure compound are optically active, e.g., they are capable of rotating the plane of plane polarized light.
  • Single enantiomers are designated according to the Cahn-Ingold-Prelog system.
  • the priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer.
  • the molecule is designated (R) and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated (S).
  • R the descending rank order of the other groups
  • S the molecule is designated (S).
  • the lowest ranking atom, D is oriented away from the viewer.
  • Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization.
  • Isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, mo st preferably at least about 99% pure, by weight.
  • Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound described herein, or a chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAICEL® CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer’s instructions.
  • a suitable chiral column such as a member of the series of DAICEL® CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer’s instructions.
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques .
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers .
  • the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [038] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; e.g., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which may optionally be unsaturated with one or more double or triple bonds, and preferably having from one to fifteen carbon atoms (z.e., C1-C15 alkyl). In certain embodiments, an alkyl comprisesone to six carbon atoms (z.e., Ci-C 6 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl (zz-propyl), 1 -methylethyl (Ao-propyl), 1 -butyl (zz-butyl), 1 -methylpropyl ( ec-butyl), 2-methylpropyl (Ao-butyl), 1 , 1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • the term “alkyl” and its equivalents encompass linear, branched, and/or cyclic alkyl groups.
  • an “alkyl” comprises both cyclic and acyclic (linear and/or branched) alkyl components.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom andthe substituent, andthatthe substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds .
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • an “acidic functional group” or similar term refers to a chemical moiety which contains at least one dissociable proton (or isotopic variant thereof), as well as to the conjugate base of such a group unless otherwise specified.
  • the dissociable proton dissociates from the chemical moiety at a pH common in aqueous systems (e.g. pHs from about 1 to about 14).
  • the dissociable proton dissociates from the chemical moiety in an aqueous system at a pH of less than 7 (e.g.
  • an acidic functional group contains the dissociable proton will depend on the conditions of the system in which the chemical moiety is present (e.g., the pH of an aqueous system containing molecule with the acidic functional group or the presence of any base molecule).
  • the term “acidic functional group” (or reference to a specific acidic functional group such as a carboxylic acid or a sulfonic acid) as used herein is intended to cover the protonated version of the moiety, the deprotonated version of the moiety, and any salt of the moiety, unless otherwise specified.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms (e.g., isotopic variant(s)).
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds .
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carb on- 14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • a or “an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more un substituted 2 to 20 membered heteroalkyls.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH 4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trim ethyl sulf onium, and the like.
  • salts and/or or “pharmacologically acceptable salts” are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge etal, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids.
  • the present disclosure includes such salts.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propri onates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.
  • the parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure.
  • the present disclosure provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure . Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms . In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of a compound to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient.
  • pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, complexing agents (e.g.
  • cyclodextrins binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.
  • preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration .
  • treating refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’ s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • the term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease.
  • treating is preventing.
  • treating does not include preventing.
  • Treating” or “treatment” as used herein also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (e.g. , not worsening) the state of disease, prevention of a disease’ s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable.
  • treatment includes any cure, amelioration, or prevention of a disease .
  • Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms (e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure), fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things.
  • "Treating” and “treatment” as used herein include prophylactic treatment.
  • Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein. The administering step may consist of a single administration or may include a series of administrations.
  • the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the compositions usedin the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime . Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treatthe patient.
  • prevent refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment. In certain embodiments, prevent refers to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state .
  • “Patient” or “subject in need thereof’ refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non -mammalian animals.
  • a patient is human.
  • a “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition).
  • An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e .g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses .
  • a prophylactically effective amount may be administered in one or more administrations .
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); an d Remington. The Science andPractice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • the therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject’s condition, and the like.
  • measurement of the serum level of an inhibitor (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been administered.
  • the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
  • therapeutically effective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals .
  • the dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. Adjusting the dose to achieve maximal therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
  • a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described herein.
  • a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or atleast 100%.
  • Therapeutic efficacy can also be expressed as “-fold” increase or decrease.
  • a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • administering means subcutaneous (i.e., “SC,” “subQ,” or “SQ”) administration, oral administration, administration as a suppository, topical contactor administration, intravenous, parenteral, intraperitoneal, intramuscular, intraosseous, intralesional, intrathecal, intracranial, intranasal, epidural, or the implantation of a slow -release device, e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g. anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease).
  • additional therapies e.g. anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease.
  • the compound of the disclosure canbe administered alone or can be coadministered to the patient.
  • Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent).
  • the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).
  • the compositions of the present disclosure can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • the compositions of the present disclosure may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
  • compositions of the present disclosure can also be delivered as microspheres for slow release in the body .
  • microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7.623- 645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12.857- 863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49.669-674, 1997).
  • the formulations of the compositions of the present disclosure can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, e.g., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resultingin endocytosis.
  • liposomes particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present disclosure into the target cells in vivo .
  • the compositions of the present disclosure can also be delivered as nanoparticles.
  • compositions described herein are administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the disclosure can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the compositions of the present disclosure can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient.
  • This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
  • the compounds described herein can be usedin combination with one another, with other active agents known to be useful in treating a mental or psychiatric disorder, a mood disorder, a neurological condition or disorder, a metabolic disorder (e.g., type 2 diabetes mellitus and/or complications thereof), endometriosis, glaucoma, pain, or an inflammatory disorder.
  • a mental or psychiatric disorder e.g., a mood disorder, a neurological condition or disorder, a metabolic disorder (e.g., type 2 diabetes mellitus and/or complications thereof), endometriosis, glaucoma, pain, or an inflammatory disorder.
  • co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week or 1 month of a second active agent.
  • Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or30 minutes of each other), or sequentially in any order.
  • co-administration can be accomplished by co-formulation, e.g., preparing a single pharmaceutical composition including both active agents.
  • the active agents can be formulated separately.
  • the active and/or adjunctive agents maybe linked or conjugated to one another.
  • the compounds described herein may be combined with treatments for infections (e.g. bacterial infections), inflammation, and/or vasodilation.
  • the compounds described herein can be administered to treat a metabolic disease or disorder (e.g., type 2 diabetes mellitus and/or complications thereof), a mental or psychiatric disorder, a mood disorder, a neurological condition or disorder, endometriosis, glaucoma, pain, or an inflammatory disorder.
  • a metabolic disease or disorder e.g., type 2 diabetes mellitus and/or complications thereof
  • a mental or psychiatric disorder e.g., a mental or psychiatric disorder, a mood disorder, a neurological condition or disorder, endometriosis, glaucoma, pain, or an inflammatory disorder.
  • the compounds disclosed herein maybe administered either alone to treat such diseases or disorders or may be co -administered with another therapeutic agent to treat such diseases or disorders.
  • the compounds disclosed herein may be co-administered with other active agents including but not limited to antidepressants, antipsychotics, anti-inflammatories, anxiolytics, and/or analgesics.
  • the compounds (e.g., flumazenil, etc.) disclosed herein maybe administered once daily until study reached endpoint, or may be administered by a continuous dose or otherwise administered over a period of time (e.g. by a wearable device accordingto a pre-programmed protocol designed to maintain a certain concentration in relevant tissues in the subject).
  • bioavailability (F) refers to the fraction of a dose of drug (e.g., epinephrine) that is absorbed from its site of administration and reaches, in an unchanged form, the systemic circulation.
  • drug e.g., epinephrine
  • absolute bioavailability is used when the fraction of absorbed drug is related to its I V. bioavailability. It may be calculated using the following formula.
  • CL refers to the rate at which a drug is eliminated divided by its plasma concentration, giving a volume of plasma from which drug is completely removed per unit of time.
  • CL is equal to the elimination rate constant (X) multiplied by the volume of distribution (Vj), wherein “Va” is the fluid volume that would be required to contain the amount of drug present in the body atthe same concentration as in the plasma.
  • apparent clearance (CL/F), refers to clearance that does not take into account the bioavailability of the drug. It is the ratio of the dose over the AUC.
  • flumazenil refers to a compound of the following structure. or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the CAS registry number for flumazenil is 78755-81-4.
  • Other names for flumazenil include, but are not limited to ethyl 8- fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate.
  • a cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
  • Cells may include prokaryotic and eukaryotic cells.
  • Prokaryotic cells include but are not limited to bacteria.
  • Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
  • Control or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples) .
  • dosage levels of flumazenil in the compositions can range from about 5 pg/kg to about 10 mg/kg, from about 0.5 mg/kgto about 5 mg/kg, from about 1 mg/kgto about 3 mg/kg, or a fixed dose from about 10-100 mg, or 20-75mg, or 3-60 mg, or 10-250 mg, or 10-400 mg, or an amount greater than 400 mg.
  • the dosages are low, in the range of 0.5-6 mg/day in a subject.
  • substantially pure indicates that a component makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total content. More typically, “substantially pure” refers to compositions in which at least 75%, at least 85%, atleast 90% or more of the total composition is the component of interest. In some cases, the polypeptide will make up greater than about 90%, or greater than about 95% of the total content of the composition (percentage in a weight per weight basis).
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.
  • species e.g., chemical compounds including biomolecules or cells
  • the term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species maybe a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway (e .g., MAP kinase pathway).
  • a signaling pathway e .g., MAP kinase pathway.
  • agonist refers to a substance capable of detectab ly increasing the expression or activity of a given gene or protein .
  • the agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist.
  • expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higherthan the expression or activity in the absence of the agonist.
  • an agonist is a molecule that interacts with a target to cause or promote an increase in the activation of the target.
  • activators are molecules that increase, activate, facilitate, enhance activation, sensitize, or up -regulate, e.g., a gene, protein, ligand, receptor, or cell.
  • the “activity” of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor; to catalytic activity; to the ability to stimulate gene expression or cell signaling, differentiation, or maturation; to antigenic activity; to the modulation of activities of other molecules; and the like.
  • osmolality as described herein is defined as the number of osmoles (Osm) of solute per kilogram of solvent (osmol/kg or Osm/kg).
  • osmolarity as described herein is defined is defined as the number of osmoles of solute per liter (L) of solution (osmol/L or Osm/L).
  • flumazenil suitable for dosing or administration by subcutaneous injection.
  • Subcutaneously deliverable flumazenil has the advantage over other forms of flumazenil (e.g. IV or IM delivery) in that it can be used outside of a hospital or clinical setting, such as at home by the subject.
  • Other formulations of flumazenil are limited by the low solubility of flumazenil in neutral solutions. Indeed, currently available USP formulations are acidic (pH ⁇ 4) and of a very low concentration ( ⁇ 0.1 mg/mL), which render them unsuitable for subcutaneous administration, as the low pH would likely cause injection site pain and discomfort and the low concentration would require a substantial volume to be delivered over the course of treatment.
  • flumazenil This high volume requirement has limited use of flumazenil to hospital settings where it can be administered by IV. Additionally, flumazenil has extremely limited oral bioavailability and a very short half-life, making oral formulations of flumazenil unrealistic solutions.
  • a pharmaceutical composition comprising: (i) flumazenil, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a form for dosing or administration by subcutaneous injection; and wherein the concentration of flumazenil in the pharmaceutical composition is greater than 0.7 mg/mL.
  • a pharmaceutical composition comprising: (i) flumazenil, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one complexing agent, wherein the pharmaceutical composition is in a form for dosing or administration by subcutaneous injection; and wherein the concentration of flumazenil in the pharmaceutical composition is greater than 0.7 mg/mL.
  • a pharmaceutical composition comprising (i) a pharmaceutical compound, wherein the pharmaceutical compound is a GABAA receptor antagonist or modulator, a GABA receptor agonist, a GABA receptor partial agonist, a GABAA receptor negative allosteric modulator or inverse agonist, or salvinorin A, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient comprises a cyclodextrin substituted with at least one acidic functional group or a conjugate base thereof or a cyclodextrin substituted with at least one polar functional group, wherein the pharmaceutical composition is in a form for dosing or administration by subcutaneous injection.
  • the at least one pharmaceutically acceptable excipient comprises a complexing agent.
  • the complexing agent is a cyclodextrin.
  • Cyclodextrins are a family of cyclic oligosaccharides comprising a macrocyclic ring of glucose or other sugar subunits joined by a-l,4 glycosidic bonds. Common forms of cyclodextrins include alpha-cyclodextrins which contain 6 glucose subunits, beta-cyclodextrins which contain 7 glucose subunits, and gamma-cyclodextrins which contain 8 glucose subunits. Cyclodextrins may be substituted or unsubstituted (e.g. have no substituents attached to the glucose monomers).
  • the complexing agent is a substituted or unsubstituted cyclodextrin.
  • the substituted cyclodextrin comprises ionic functional groups.
  • the ionic functional groups are carboxylate groups, phosphate groups, phosphonate groups, sulfate groups, or sulfonate groups.
  • cyclodextrin is substituted with sulfonate functional groups.
  • the cyclodextrin is substituted with at least 1, atleast 2, at least 3, at least4, atleast 5, at least 6, at least 7, or at least 8 ionic functional groups.
  • the cyclodextrin is substituted with from about2 to about 8 ionic functional groups.
  • the cyclodextrin is substituted with from about 4 to about 8 ionic functional groups .
  • the cyclodextrin is substituted with at least one acidic functional group.
  • the acidic functional group is a carboxylic acid, a phosphonic acid, or a sulfonic acid.
  • the acidic functional group is a sulfonic acid.
  • the cyclodextrin is substituted with atleast 1, at least 2, at least 3, atleast 4, at least 5, atleast 6, at least 7, or at least 8 acidic functional groups.
  • the cyclodextrin is substituted with from about 2 to about 8 acidic functional groups.
  • the cyclodextrin is substituted with from about 4 to about 8 acidic functional groups.
  • the cyclodextrin is a sulfobutyl-ether substituted cyclodextrin.
  • the cyclodextrin is a sulfobutyl-ether-alpha-cyclodextrin (SBEACD), sulf obutyl-ether-beta-cy clod extrin (SBEBCD), sulfobutyl-ether-gamma-cyclodextrin (SBEGCD).
  • the cyclodextrin is sulf obutyl-ether-beta-cyclod extrin (SBEBCD).
  • the complexing agent is a free acid version of a cyclodextrin substituted with at least one acidic functional group .
  • the complexing agent can act as a counterion to flumazenil which has become protonated .
  • at least a portion of the flumazenil is protonated.
  • the free acid version of the cyclodextrin is used in an intermediate step in the preparation of the pharmaceutical formulation.
  • Such a free acid version of an acid substituted cyclodextrin can be used to initially solubilize the flumazenil prior to the addition of other excipients, such as additional buffers which can be u sed to raise the pH of the intermediate protonated flumazenil, which can result in a soluble complex of flumazenil while mitigating the high osmolality which would result from a direct mixing of a salt form of the cyclodextrin substituted with one or more acidic functional groups (e .g. a sodium salt) at the same concentration.
  • additional buffers which can be u sed to raise the pH of the intermediate protonated flumazenil, which can result in a soluble complex of flumazenil while mitigating the high osmolality which would result from a direct mixing of a salt form of the cyclodextrin substituted with one or more acidic functional groups (e .g. a sodium salt) at the same concentration.
  • acidic functional groups e .g
  • the complexing agent is a cyclodextrin substituted with at least one polar functional groups.
  • the polar functional group is non -ionic.
  • the polar functional group is a hydroxy -alkyl group, an alkoxy alkyl group, a thioether group, an ester group, an amide group, a sulfonamide group, a sulfonate ester group, or any combination thereof.
  • the polar functional group is a hydroxyalkyl group.
  • the polar functional group is a C 2 -C 6 hydroxyalkyl group.
  • the polar functional group is a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group, or a hydroxy hexyl group. In some embodiments, the polar functional group is a hydroxypropyl group.
  • the complexing agent is a hydroxybutyl substituted cyclodextrin.
  • the complexing agent is a hydroxypropyl-alpha-cyclodextrin (HPACD), a hydroxypropyl-beta-cyclodextrin (HPBCD), or a hydroxypropyl-gamma-cyclodextrin (HPGCD).
  • HPACD hydroxypropyl-alpha-cyclodextrin
  • HPBCD hydroxypropyl-beta-cyclodextrin
  • HPGCD hydroxypropyl-gamma-cyclodextrin
  • the molar ratio of complexing agent to flumazenil is about 1 : 10 to about 10:1. In some embodiments, the molar ratio of flumazenil to complexing agent is about 1 : 10 to about 1 :5, about 1 : 10 to about 1 :1, about 1 : 10 to about 2:1, about 1 : 10 to about 3 :1, about 1 : 10 to about 4:1, about 1 : 10 to about 5:1, about 1 : 10 to about 10:1, about 1 :5 to about 1 :1, about 1 :5 to about2:l, about 1 :5 to about3 :1, about 1 :5 to about 4:1, about 1 :5 to about 5:1, about 1 :5 to about 10:1, about 1 : 1 to about 2:1, about 1 : 1 to about 3 :1, about 1 : 1 to about 4:1, about 1 : 1 to about 5 :1, about 1 : 1 to about 10:1, about 2 : 1 to about 3 :1, about 2 : 1 to about 4:1, about 1 : 1 to
  • the molar ratio of flumazenil to complexing agent is about 1 :10, about 1 :5, about 1 :1, about2:l, about 3 :l, about4:l, about 5:l, or about 10:1. In some embodiments, the molar ratio of flumazenil to complexing agent is at least about 1 :10, about 1 :5, about 1 :1, about 2:1, about 3 :1, about 4:1, or about 5 :1. In some embodiments, the molar ratio of flumazenil to complexing agent is at most about 1 :5, about 1 :1, about 2:1, about 3 :1, about 4:1, about 5 : 1 , or about 10 : 1. In some embodiments, the complexing agent is HPBCD.
  • the complexing agent is SBEBCD.
  • the concentration of the complexing agent is about 10 mg/mLto about 200 mg/mL. In some embodiments, the concentration of the complexing agent is about 10 mg/mL to about25 mg/mL, about 10 mg/mLto about 50 mg/mL, about 10 mg/mLto about 75 mg/mL, about 10 mg/mLto about 100 mg/mL, about 10 mg/mLto about 125 mg/mL, about 10 mg/mL to about 150 mg/mL, about 10 mg/mLto about 175 mg/mL, about 10 mg/mLto about 200 mg/mL, about25 mg/mLto about 50 mg/mL, about25 mg/mLto about75 mg/mL, about 25 mg/mL to about 100 mg/mL, about 25 mg/mLto about 125 mg/mL, about 25 mg/mLto about 150 mg/mL, about25 mg/mLto about 175 mg/mL
  • the concentration of the complexing agent is about 10 mg/mL, about 25 mg/mL, about 50 mg/mL, about 75 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, or about 200 mg/mL. In some embodiments, the concentration of the complexing agent is at least about 10 mg/mL, about 25 mg/mL, about 50 mg/mL, about 75 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, or about 175 mg/mL.
  • the concentration of the complexing agent is at most about 25 mg/mL, about 50 mg/mL, about 75 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, or about 200 mg/mL.
  • the complexing agent is HPBCD. In some embodiment, the complexing agent is SBEBCD.
  • the concentration of HPBCD is about 10 mg/mL to about 300 mg/mL. In some embodiments, the concentration of HPBCD is about 10 mg/mLto about 50 mg/mL, about 10 mg/mLto about 100 mg/mL, about 10 mg/mLto about 150 mg/mL, about 10 mg/mL to about 200 mg/mL, about 10 mg/mLto about 250 mg/mL, about 10 mg/mLto about 300 mg/mL, about 50 mg/mLto about 100 mg/mL, about 50 mg/mLto about 150 mg/mL, about 50 mg/mL to about 200 mg/mL, about 50 mg/mLto about 250 mg/mL, about 50 mg/mLto about 300 mg/mL, about 100 mg/mLto about 150 mg/mL, about lOO mg/mLto about 200 mg/mL, about 100 mg/mLto about250 mg/mL, about 100 mg/mLto about300 mg/mL, about 150
  • the concentration of HPBCD is about 10 mg/mL, about 50 mg/mL, about lOO mg/mL, about 150 mg/mL, about200 mg/mL, about 250 mg/mL, or about 300 mg/mL. In some embodiments, the concentration of HPBCD is at least about 10 mg/mL, about 50 mg/mL, about 100 mg/mL, about 150 mg/mL, about 200 mg/mL, or about 250 mg/mL. In some embodiments, the concentration of HPBCD is at most about 50 mg/mL, about 100 mg/mL, about 150 mg/mL, about 200 mg/mL, about 250 mg/mL, or about 300 mg/mL.
  • the concentration of flumazenil is greater than 0.7 mg/mL. In some embodiments, the concentration of flumazenil is at least 0.8 mg/mL In some embodiments, the concentration of flumazenil is at least 0.9 mg/mL In some embodiments, the concentration of flumazenil is at least 1.0 mg/mL. In some embodiments, the concentration of flumazenil is at least 1.
  • the concentration of flumazenil is at least 1 .2 mg/mL In some embodiments, the concentration of flumazenil is at least 1 .3 mg/mL In some embodiments, the concentration of flumazenil is at least 1.4 mg/mL In some embodiments, the concentration of flumazenil is at least 1.4 mg/mL In some embodiments, the concentration of flumazenil is at least 1.6 mg/mL In some embodiments, the concentration of flumazenil is at least 1 .7 mg/mL In some embodiments, the concentration of flumazenil is at least 1.8 mg/mL In some embodiments, the concentration of flumazenil is at least 1.9 mg/mL.
  • the concentration of flumazenil is at least 2.0 mg/mL. In some embodiments, the concentration of flumazenil is at least 2.2 mg/mL. In some embodiments, the concentration of flumazenil is at least 2.4 mg/mL. In some embodiments, the concentration of flumazenil is at least 2.6 mg/mL. In some embodiments, the concentration of flumazenil is at least 2.8 mg/mL. In some embodiments, the concentration of flumazenil is at least 3.0 mg/mL. In some embodiments, the concentration of flumazenil is at least about 4.0 mg/mL. In some embodiments, the concentration of flumazenil is at least about 5.0 mg/mL.
  • the concentration of flumazenil is about 0.8 mg/mL to about 10 mg/mL. In some embodiments, the concentration of flumazenil is about 0.8 mg/mL to about 1 mg/mL, about 0.8 mg/mL to about 1.2 mg/mL, about 0.8 mg/mL to about 1.5 mg/mL, about 0.8 mg/mL to ab out 1 .8 mg/mL, ab out 0.8 mg/mL to ab out 2 mg/mL, ab out 0.8 mg/mL to ab out 2.5 mg/mL, about 0.8 mg/mL to about 3 mg/mL, about 0.8 mg/mL to about 4 mg/mL, about 0.8 mg/mL to about 5 mg/mL, about 0.8 mg/mL to about 7.5 mg/mL, about 0.8 mg/mL to about 10 mg/mL, about 1 mg/mL to about 1 .2 mg/mL, about 1 mg/mL to about 1.5 mg/mL, about 1 mg/m/m
  • the concentration of flumazenil is about 0.8 mg/mL, about 1 mg/mL, about 1 .2 mg/mL, about 1.5 mg/mL, about 1.8 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 7.5 mg/mL, or about 10 mg/mL.
  • the concentration of flumazenil is at least about 0.8 mg/mL, about 1 mg/mL, ab out 1.2 mg/mL, about 1.5 mg/mL, about 1.8 mg/mL, about2 mg/mL, about 2.5 mg/mL, about3 mg/mL, about4 mg/mL, about 5 mg/mL, or about 7.5 mg/mL.
  • the concentration of flumazenil is at most about 1 mg/mL, about 1.2 mg/mL, about 1.5 mg/mL, about 1.8 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 7.5 mg/mL, or about 10 mg/mL.
  • the concentration of flumazenil is from about 1.0 mg/mL to about 10 mg/mL. In some embodiments, the concentration of flumazenil is from about 1.0 mg/mL to about 8 mg/mL. In some embodiments, the concentration of flumazenil is from about 1.0 mg/mL to about 5 mg/mL. In some embodiments, the concentration of flumazenil is from about 1.5 mg/mL to about 10 mg/mL. In some embodiments, the concentration of flumazenil is from about 1.5 mg/mL to about 8 mg/mL. In some embodiments, the concentration of flumazenil is from about 1.5 mg/mL to about 5 mg/mL.
  • the concentration of flumazenil is from about2.0mg/mL to about 10 mg/mL. In some embodiments, the concentration of flumazenil is from about 2.0 mg/mL to about 8 mg/mL. In some embodiments, the concentration of flumazenil is from about 2.0 mg/mL to about 5 mg/mL. In some embodiments, the concentration of flumazenil is from about 2.5 mg/mL to about 10 mg/mL In some embodiments, the concentration of flumazenil is from about 2.5 mg/mL to about 8 mg/mL. In some embodiments, the concentration of flumazenil is from about 2.5 mg/mL to about 5 mg/mL.
  • the concentration of flumazenil is from about 3.0 mg/mL to about 10 mg/mL In some embodiments, the concentration of flumazenil is from about 3.0 mg/mL to about 8 mg/mL. In some embodiments, the concentration of flumazenil is from about 3.0 mg/mL to about 5 mg/mL.
  • the pH of the pharmaceutical composition is about4 to about 10. In some embodiments, the pH of the pharmaceutical composition is about 4 to about 5, about 4 to about 6, about 4 to about 7, about 4 to about 8, about 4 to about 9, about 4 to about 10, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 5 to about 9, about 5 to about 10, about 6 to about 7, about 6 to about 8, about 6 to about 9, about 6 to about 10, about 7 to about 8, about 7 to about 9, about 7 to about 10, about 8 to about 9, about 8 to about 10, or about 9 to about 10. In some embodiments, the pH of the pharmaceutical composition is about4, about 5, about 6, about 7, about 8, about 9, or about 10. In some embodiments, the pH of the pharmaceutical composition is at least about 4, about 5, about 6, or about 7. In some embodiments, the pH of the pharmaceutical composition is at most about 7, about 8, about 9, or about 10.
  • the pH of the pharmaceutical composition is about 6 to about 8. In some embodiments, the pH of the pharmaceutical composition is about 6.5 to about 8. In some embodiments, the pH of the pharmaceutical composition is about 7 to about 8. In some embodiments, the pH of the pharmaceutical composition is about 7 to about 8.5. In some embodiments, the pH of the pharmaceutical composition is about 7 to about 9.
  • the pH of the pharmaceutical composition is about 5 to about 8. In some embodiments, the pH of the pharmaceutical composition is about 5 to about 7.5. In some embodiments, the pH of the pharmaceutical composition is about 5 to about 7. In some embodiments, the pH of the pharmaceutical composition is about 5 to about 6.5. In some embodiments, the pH of the pharmaceutical composition is about 5 to about 6. In some embodiments, the pH of the pharmaceutical composition is about 5.5 to about 8. In some embodiments, the pH ofthe pharmaceutical composition is about 5.5 to about7.5. In some embodiments, the pH ofthe pharmaceutical composition is about 5.5 to about 7.0. In some embodiments, the pH ofthe pharmaceutical composition is about 5.5 to about6.5.
  • the osmolality of the pharmaceutical composition is about 250 mOsm/kgto about 500 mOsm/kg. In some embodiments, the osmolality of the pharmaceutical composition is about 250 mOsm/kgto about275 mOsm/kg, about250 mOsm/kgto about 300 mOsm/kg, about250 mOsm/kgto about 325 mOsm/kg, about250 mOsm/kgto about 350 mOsm/kg, about 250 mOsm/kgto about 400 mOsm/kg, about 250 mOsm/kgto about 500 mOsm/kg, about275 mOsm/kgto about 300 mOsm/kg, about275 mOsm/kgto about 325 mOsm/kg, about275 mOsm/kgto about 350 mOsm/kg, about275 mOsm/kgto about400 mOsm/
  • the osmolality of the pharmaceutical composition is about 250 mOsm/kg, about 275 mOsm/kg, about 300 mOsm/kg, about 325 mOsm/kg, about 350 mOsm/kg, about 400 mOsm/kg, or about 500 mOsm/kg. In some embodiments, the osmolality of the pharmaceutical composition is at least about250 mOsm/kg, about275 mOsm/kg, about 300 mOsm/kg, about 325 mOsm/kg, about 350 mOsm/kg, or about 400 mOsm/kg.
  • the osmolality of the pharmaceutical composition is at most about 275 mOsm/kg, about 300 mOsm/kg, about 325 mOsm/kg, about 350 mOsm/kg, about 400 mOsm/kg, or about 500 mOsm/kg.
  • the osmolality of the pharmaceutical composition is about 300 mOsm/kg. In some embodiments, the osmolality of the pharmaceutical composition is from about 275 to about 300 mOsm/kg. In some embodiments, the osmolality of the pharmaceutical composition is from about 275 to about 325 mOsm/kg. In some embodiments, the osmolality of the pharmaceutical composition is from about 275 to about 350 mOsm/kg. In some embodiments, the osmolality of the pharmaceutical composition is from about 250 to about 300 mOsm/kg. In some embodiments, the osmolality of the pharmaceutical composition is from about 250 to about 325 mOsm/kg. In some embodiments, the osmolality of the pharmaceutical composition is from about 250 to about 350 mOsm/kg.
  • the viscosity of the pharmaceutical composition is about 1 centipoise (cP) to about 3 cP. In some embodiments, the viscosity of the pharmaceutical composition is about 1 cP to about 1 .5 cP, about 1 cP to about 1 .7 cP, about 1 cP to about 1 .8 cP, about 1 cP to about 1.9 cP, about 1 cP to about 2 cP, about 1 cP to about 2.1 cP, ab out 1 cP to about 2.2 cP, about 1 cP to about 2.5 cP, about 1 cP to about 3 cP, about 1.5 cP to about 1.7 cP, about 1.5 cPto about 1.8 cP, about 1.5 cPto about 1.9 cP, about 1.5 cP to about2 cP, about 1.5 cP to about2.1 cP, about 1.5 cP to about2.2 cP, about 1.5 cPto
  • the viscosity of the pharmaceutical composition is about 1 cP, about 1.5 cP, about 1 .7 cP, about 1.8 cP, about 1 .9 cP, about2 cP, about2.1 cP, about 2.2 cP, about 2.5 cP, or about 3 cP. In some embodiments, the viscosity of the pharmaceutical composition is at least about 1 cP, about 1 .5 cP, about 1 .7 cP, about 1.8 cP, about 1.9 cP, about2 cP, about2.1 cP, about2.2 cP, or about2.5 cP.
  • the viscosity of the pharmaceutical composition is at most about 1.5 cP, about 1.7 cP, about 1.8 cP, about 1.9 cP, about 2 cP, about 2.1 cP, about 2.2 cP, about 2.5 cP, or about 3 cP.
  • the viscosity of the pharmaceutical composition is less than about 3 cP. In some embodiments, the viscosity of the pharmaceutical composition is less than about 2.9 cP. In some embodiments, the viscosity of the pharmaceutical composition is less than about 2.8 cP. In some embodiments, the viscosity of the pharmaceutical composition is less than about 2.7 cP In some embodiments, the viscosity of the pharmaceutical composition is less than about 2.6 about cP. In some embodiments, the viscosity of the pharmaceutical composition is less than about 2.5 cP. In some embodiments, the viscosity of the pharmaceutical composition is less than about 2.4 cP. In some embodiments, the viscosity of the pharmaceutical composition is less than
  • the viscosity of the pharmaceutical composition is less than 2.2 cP. In some embodiments, the viscosity of the pharmaceutical composition is less than about 2.1 cP. In some embodiments, the viscosity of the pharmaceutical composition is less than about 2 cP.
  • the pharmaceutical composition comprises a minimal amount of saline.
  • the pharmaceutical composition comprises a salinity of less than about 0.8 % w/v, less than about 0.7 % w/v, less than about 0.6 % w/v, less than about 0.5 % w/v, less than about 0.4 % w/v, less than about 0.3 % w/v, less than about 0.2 % w/v, or less than about 0. 1 % w/v of sodium chloride.
  • the pharmaceutical composition further comprises a preservative.
  • the preservative is benzethonium chloride.
  • the benzethonium chloride is present in an amount of about 0.1 mg/mLto about 1 mg/mL.
  • the preservative is benzethonium chloride, benzalkonium chloride, or chloroxylenol.
  • Other preservatives include benzyl alcohol, methyl parabens, ethyl or n-propyl, and p-hydroxybenzoate.
  • preservatives are antimicrobial agents, including, but not limited to.
  • the preservative is present in an amount of about 0.1 mg/mL to about 1 mg/mL.
  • the preservative is present in an amount of about 0.1 mg/mL to about 0.2 mg/mL, about 0.1 mg/mLto about 0.3 mg/mL, about 0.1 mg/mLto about 0.4 mg/mL, about 0.1 mg/mLto about 0.5 mg/mL, about 0.1 mg/mL to about 0.6 mg/mL, about 0.1 mg/mL to about 0.7 mg/mL, about 0.1 mg/mL to about 0.8 mg/mL, about 0.1 mg/mLto about 0.9 mg/mL, about 0.1 mg/mLto about 1 mg/mL, about 0.2 mg/mLto about 0.3 mg/mL, about 0.2 mg/mLto about 0.4 mg/mL, about 0.2 mg/mLto about 0.5 mg/mL, about 0.2 mg/mL to about 0.6 mg/mL, about 0.2 mg/mL to about 0.7 mg/mL, about 0.2 mg/mL to about 0.8 mg/mL, about 0.1 mg/
  • the preservative is present in an amount of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, or about 1 mg/mL. In some embodiments, the preservative is present in an amount of about at least about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, or about 0.9 mg/mL.
  • the preservative is present in an amount of about at most about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, or about 1 mg/mL
  • the pharmaceutical composition further comprises a base, a buffer, or a combination thereof.
  • the pharmaceutical composition further comprises at least one amino acid, or a functional variant thereof.
  • the at least one amino acid enhances the solubility of flumazenil.
  • the at least one amino acid acts as a solubility enhancer for combination use with a complexing agent.
  • the at least one amino acid includes an alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or a functional variant thereof.
  • the pharmaceutical composition further comprises an emulsifying agent, a surfactant, a solubilizing agent, a co-solvent or a combination thereof.
  • the co-solvent is ethanol, propylene glycol, tween 20, tween 80, or glycerin.
  • the pharmaceutical composition is adapted to be administered to a subject over a period of time.
  • Such administration can be a continuous dose (e.g. at a constant rate) or can be administered according to a pre-determined schedule (e.g. bolus additions of the pharmaceutical composition over a set schedule over the period of time).
  • the period of time is at least about 2 days. In some embodiments, the period of time is about 2 days. In some embodiments, the period of time is about 3 days. In some embodiments, the period of time is about 36 hours to about 72 hours.
  • the period of time is about 36 hours to about 42 hours, about 36 hours to about48 hours, about 36 hours to about 54 hours, about 36 hours to about 60 hours, about 36 hours to about 66 hours, about 36 hours to about 72 hours, about 42 hours to about 48 hours, about 42 hours to about 54 hours, about 42 hours to about 60 hours, about 42 hours to about 66 hours, about 42 hours to about 72 hours, about 48 hours to about 54 hours, about 48 hours to about 60 hours, about 48 hours to about 66 hours, about 48 hours to about 72 hours, about 54 hours to about 60 hours, about 54 hours to about 66 hours, about 54 hours to about 72 hours, about 60 hours to about 66 hours, about 60 hours to about 72 hours, or about 66 hours to about 72 hours.
  • the period of time is about 36 hours, about 42 hours, about 48 hours, about 54 hours, about 60 hours, about 66 hours, or about 72 hours. In some embodiments, the period of time is at least about 36 hours, about 42 hours, about 48 hours, about 54 hours, about 60 hours, or about 66 hours. In some embodiments, the period of time is at most about 42 hours, about 48 hours, about 54 hours, about 60 hours, about 66 hours, or about 72 hours. [H9] In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of at least 0.5 mg of flumazenil. In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of at least 1 mg of flumazenil.
  • the pharmaceutical composition is adapted to deliver a daily dose of at least 1.5 mg of flumazenil. In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of at least 2.0 mg of flumazenil. In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of at least 2.5 mg of flumazenil. In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of at least 3.0 mg of flumazenil. In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of flumazenil of about 0.5 mg to about 4 mg.
  • the pharmaceutical composition is adapted to deliver a daily dose of flumazenil of about 0.5 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 0.5 mgto about2 mg, about 0.5 mgto about2.5 mg, about 0.5 mgto about 3 mg, about 0.5 mgto about 3.5 mg, about 0.5 mgto about 4 mg, about 1 mgto about 1.5 mg, about 1 mg to about 2 mg, about 1 mg to about 2.5 mg, about 1 mgto about 3 mg, about 1 mgto about
  • the pharmaceutical composition is adapted to deliver a daily dose of flumazenil of about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, or about 4 mg. In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of flumazenil of atleast about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about
  • the pharmaceutical composition is adapted to deliver a daily dose of flumazenil of at most about 1 mg, about 1.5 mg, about 2 mg, about2.5 mg, about 3 mg, about 3.5 mg, or about 4 mg. In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of flumazenil of at least about 4 mg, at least about 4.5 mg, at least about 5 mg, at least about 5.5 mg, or at least about 6 mg. In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of flumazenil of from about 0.5 mgto about 6 mg. In some embodiments, the pharmaceutical composition is adapted to deliver a daily dose of flumazenil of up to about 10 mg.
  • the pharmaceutical composition is adapted to deliver a daily dose of a therapeutically effective amount of the GABA receptor modulator.
  • the daily dose required for the GABA receptor modulator will depend upon the GABA receptor modulator selected based on numerous factors, including its potency, pharmacokinetic properties, and the severity of symptoms of the patient.
  • the daily dose which can be delivered according to the formulations and methods provided herein cam be ascertained by calculations involving the relevant parameters provided herein (e.g. concentration of the GABA receptor modulator in the formulation, the size of the wearable reservoir, etc.).
  • the daily dose can range from 0.01 mg and lower to upwards of 3000 mg.
  • the pharmaceutical composition is adapted to be administered to be delivered by a wearable device, such as a small pump.
  • a wearable device should have a sufficiently small footprint to allow the wearer to carry on their daily life with minimal disruption. Thus, the maximum volume of such a device should be kept to a minimum.
  • the wearable device has a reservoir of the pharmaceutical composition of less than 10 mL. In some embodiments, the wearable device has a reservoir of the pharmaceutical composition of less than 3 mL, 4 mL, 5 mL, 7.5 mL, 10 mL, 12.5 mL, 15 mL, 20 mL, 25 mL or 30 mL.
  • the wearable device has a reservoir of the pharmaceutical composition of about 2-3 mL, about 2-4 mL, about 2-5 mL, about 2-1 O mL, about 3-4 mL, about 3-5 mL, or about 3 -10 mL.
  • the reservoir volume as listed above reflects the maximum volume of the reservoir.
  • the pharmaceutical compound is another compound that modulates one or more GABA receptors, such as the GABA A receptor.
  • the pharmaceutical compound is a GAB A A receptor antagonist or modulator, a GABA receptor agonist, a GABA receptor partial agonist, a GABA A receptor negative allosteric modulator or inverse agonist, or salvinorin A, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the GABA A receptor antagonist or modulator is flumazenil or pentylenetetrazol.
  • the GABA receptor agonist is muscimol, thiomuscimol, or gaboxadol.
  • the GAB A receptor partial agonist is bretazenil, imidazenil, FG 8205 (7-chloro-5-methyl-3-(5-propan-2-yl-l,2,4-oxadiazol- 3-yl)-4H-imidazo[l,5-a][l,4]benzodiazepin-6-one), abecarnil, NS 2710 (l-[l-[3-(3- pyridyl)phenyl]benzimidazol-5-yl]ethanone O-ethyloxime), RWJ-51204 (5-ethoxymethyl-7- fluoro-3-oxo-l,2,3,5-tetrahydrobenzo[4,5] imidazo[l,2a]pyridine-4-N-(2- fluorophenyl)carboxamide), or premazepam.
  • the GAB A A receptor negative allosteric modulator or inverse agonist is bemegride, flurothyl, or pentylenetetrazol.
  • the a5 subunit containing GAB A A receptor selective compound is basmisanil, a5IA (3-(5-methylisoxazol-3-yl)-6-[(l-methyl-lH-l,2,3-triazol-4- yl)methoxy][l,2,4]triazolo[3,4-a]phthalazine), L-655,708, MRK-016, PWZ-029, a Pyridazine, Ro4938581, TB-21007, FG-7142 (N-Methyl-9H-pyrido[5,4-b]indole-3-carboxamide), Rol6- 0154 (ethyl 7-iodanyl-5-methyl-6-oxo-4H-imidazo[l,5-a][l
  • the compounds (e.g., GABA receptor modulators (e.g., flumazenil)) of the present disclosure may be in the form of compositions suitable for administration to a subject.
  • compositions are “pharmaceutical compositions” comprising a compound (e.g., GABA receptor modulators (e.g., flumazenil)) and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients.
  • the compounds e.g., GABA receptor modulators (e.g., flumazenil)
  • the pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.
  • compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.
  • the cosolvent comprises PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cremephor, glycerin, benzyl alcohol, dimethylacetamide (DMA), N-methyl- 2 -pyrrolidone (NMP), tert-butanol, or combinations thereof.
  • the dosage form or pharmaceutical composition comprises a surface-active agent.
  • the surface-active agent comprises polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate, polyoxyethylene sorbitan monolaurate (Tween 20), lecithin, polyoxyethylenepolyoxypropylene copolymers (Pluronicsl), or combinations thereof.
  • the dosage form or pharmaceutical composition comprises a non-ionic surfactant.
  • the non- ionic surfactant comprises CremophorRH40, CremophorRH60, d -alpha -topoph erol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, or combinations thereof.
  • the GABA receptor modulator is flumazenil.
  • the GABA receptor modulator is a GABAA receptor antagonist or modulator, a GABA receptor agonist, a GABA receptor partial agonist, a GABAA receptor negative allosteric modulator or inverse agonist, or salvinorin A, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the GABAA receptor antagonist or modulator is flumazenil or pentylenetetrazol.
  • the GABA receptor agonist is muscimol, thiomuscimol, or gaboxadol.
  • the GABA receptor partial agonist is bretazenil, imidazenil, FG 8205 (7-chloro-5- methyl-3-(5-propan-2-yl-l,2,4-oxadiazol-3-yl)-4H-imidazo[l,5-a][l,4]benzodiazepin-6-one), abecarnil, NS 2710 (l -[l-[3-(3-pyridyl)phenyl]benzimidazol-5-yl]ethanone O-ethyloxime), RWJ-51204 (5 -ethoxy methyl-7 -fluoro-3 -oxo- 1 ,2,3, 5 -tetrahydrob enzo[4,5 ] imidazo[l,2a]pyridine-4-N-(2-fluorophenyl)carboxamide), or premazepam.
  • the GABA A receptor negative allosteric modulator or inverse agonist is bemegride, flurothyl, or pentylenetetrazol.
  • the a5 subunit containing GAB AA receptor selective compound is basmisanil, a5IA (3-(5-methylisoxazol-3-yl)-6-[(l- methyl-lH-l,2,3-triazol-4-yl)methoxy][l,2,4]triazolo[3,4-a]phthalazine), L-655,708, MRK-016, PWZ-029, a Pyridazine, Ro4938581, TB-21007, FG-7142 (N-Methyl-9H-pyrido[5,4-b]indole-3- carboxamide), Rol6-0154 (ethyl 7-iodanyl-5-methyl-6-oxo-4H-imidazo[l,5- a][l,4
  • the pharmaceutical composition comprises one or more cosolvents, solubilization/solubilizing agents, stabilization agents, antioxidants, preservatives, cryoprotectants, lyoprotectants, bulking agents, tonicity -adjusting agents, or antimicrobial agents.
  • the pharmaceutical composition comprises at least one cosolvent.
  • the pharmaceutical composition comprises at least one solubilizing agent.
  • the pharmaceutical composition comprises at least one stabilization agent.
  • the pharmaceutical composition comprises at least one antioxidant.
  • the pharmaceutical composition comprises at least one preservative.
  • the pharmaceutical composition comprises at least one cryoprotectant.
  • the pharmaceutical composition comprises at least one lyoprotectant.
  • the pharmaceutical composition comprises at least one bulking agent.
  • the pharmaceutical composition comprises at least one tonicity-adjusting agent.
  • the pharmaceutical composition comprises at least one antimicrobial agent.
  • the formulation or pharmaceutical composition is a pharmaceutical composition.
  • the formulation is in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension maybe formulated accordingto the known art using those suitable dispersing or wetting agents and suspending agents mentioned herein.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butane diol.
  • Acceptable diluents, solvents and dispersion media include water, Ringer's solution, isotonic sodium chloride solution, Cremophor®EL (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e .g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium; for this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid, find use in the preparation of injectables.
  • Prolonged absorption of particular injectable formulations canbe achievedby including an agent that delays absorption (e .g., aluminum monostearate or gelatin).
  • the formulation comprises a cosolvent.
  • a suitable co-solvent is propylene glycol, glycerin, ethanol, polyethylene glycol (300 and 400), Sorbitol, dimethylacetamide, CremophorEL, or A-methyl-2- pyrrolidone, or dimethylsulfoxide.
  • the formulation or pharmaceutical composition is an aqueous suspension.
  • Aqueous suspensions contain active materials in admixture with excipients suitable for the manufacture thereof.
  • excipients canbe suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, poly vinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., polyoxy-ethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters
  • the formulation or pharmaceutical composition comprises a stabilization agent.
  • the formulation comprises a surface -active solubilization agent.
  • Surface-active solubilization agents include, but are not limited to. polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate, polyoxyethylene sorbitan monolaurate (Tween 20), lecithin, and Poly oxy ethylene-poly oxypropylene copolymers (Pluronicsl).
  • the formulation comprises a non-ionic surfactant solubilization agent.
  • Non-ionic surfactants include, but are not limited.
  • the formulation comprises a phospholipid solubilizing agent such as, hydrogenated soy phosphatidylcholine, phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, or L-alpha-dimyristoylphosp hatidyl glycerol.
  • a phospholipid solubilizing agent such as, hydrogenated soy phosphatidylcholine, phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, or L-alpha-dimyristoylphosp hatidyl glycerol.
  • the formulation or pharmaceutical composition comprises a complexation agent.
  • the complexation agent is hydroxypropyl-b- cyclodextrin, bulfobutylether-b-cyclodextrin(Captisoll), or polyvinylpyrrolidone.
  • the complexation agent is an amino acid such as, arginine, lysine, or histidine.
  • the formulation or pharmaceutical composition comprises a cyclodextrin excipient.
  • Cyclodextrin excipients are used to enhance the stability, tolerability and absorption of compounds in parenteral aqueous solutions. Common cyclodextrin excipients include but are not limited to.
  • alpha-Cyclodextrin alpha-CD
  • beta-Cyclodextrin beta-Cyclodextrin
  • gamma-CD Diethyl-ethyl-beta-cyclodextrin(DE-beta-CD)
  • Dimethyl-ethyl- beta-cyclodextrin DM-beta-CD
  • Hydroxypropyl-beta-cyclodextrin HP -beta-CD
  • Hydroxypropyl -gamma-cyclodextrin HP -gamma-CD
  • Methyl-b -cyclodextrin M-beta-CD
  • Sulfobutylether-beta-cyclodextrin SBE-beta-CD
  • Randomly methylated-beta-CD RM-beta- CD
  • Maltosyl-beta-CD mal -beta-CD
  • the formulations or pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these .
  • Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the formulation or pharmaceutical composition typically comprises a therapeutically effective amount of an active compound (e.g. a GABA receptor modulator, such as flumazenil), or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically and physiologically acceptable formulation agents.
  • an active compound e.g. a GABA receptor modulator, such as flumazenil
  • a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof e.g. a GABA receptor modulator, such as flumazenil
  • Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants.
  • a suitable vehicle may be physiological saline solution or citrate-buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.
  • the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.
  • Acceptable buffering agents include, for example, a triethanolamine (Tris) buffer, histidine, bicarbonate; N - (2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N- Morpholino)ethanesulfonic acid (MES); 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES); 3-(N-Morpholino)propanesulfonic acid (MOPS); and N-tris[Hydroxymethyl]methyl-3- aminopropanesulfonic acid (TAPS).
  • Tris triethanolamine
  • HEPES 2-(N- Morpholino)ethanesulfonic acid
  • MES 2-(N-Morpholino)ethanesulfonic acid sodium salt
  • MOPS 3-(N-Morpholino)propanesulfonic acid
  • TAPS N-tris[Hydroxy
  • APIs active pharmaceutical ingredients
  • Weak acids or weak bases can exist in an un -ionized form or as an ionized complex prepared by the addition of a base or acid respectively.
  • the resultant complex is stabilized by ionic interactions and is known as a salt.
  • This complex exists via an ionic bond between an ionized API and an oppositely charged counterion. Salts offer a number of advantages over their un-ionized counterparts.
  • the choice of counterion can have a large influence on the salts properties and the use of a given salt form of a given API in a pharmaceutical product is influenced and guided by a number of factors for example stability (photo, hydrolytic and thermal), solubility, physicochemical properties, solid state properties (crystallinity, polymorphism, particle size, crystal morphology, melting point, compactability), production considerations (e .g., ease of handling and processing), dissolution rate, modulation of drug release, compatibility with excipients and containers, ease and consistency of production, desired route of administration, and organoleptic factors (e.g., taste).
  • salt can influence pain and irritation atthe injection site.
  • a pharmaceutical composition After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready -to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form.
  • the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampule, syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.
  • a single-use container e.g., a single-use vial, ampule, syringe, or autoinjector (similar to, e.g., an EpiPen®)
  • a multi-use container e.g., a multi-use vial
  • Formulations or pharmaceutical compositionscan also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
  • a controlled release formulation including liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
  • a time-delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed.
  • Any drug delivery apparatus may be used to deliver a GABA receptor modulator, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan.
  • the formulation or pharmaceutical composition is stored in a reservoir of the drug delivery device. In some embodiments, the formulation is stored in a cartridge that is insertable and/or attachable to the drug delivery device. In some embodiments, the cartridge and/or drug delivery device comprises a product label for intramuscular injection . In some embodiments, the cartridge and/or drug delivery device comprises a product label for subcutaneous injection. In some embodiments, the cartridge and/or drug delivery device comprises a product label for intravenous injection. In some embodiments, disclosed herein is a kit comprising a product label for intramuscular injection . In some embodiments, disclosed herein is a kit comprising a product label for subcutaneous injection. In some embodiments, disclosed herein is a kit comprising a product label for intravenous injection.
  • the formulation or pharmaceutical composition is a liquid formulation comprising flumazenil.
  • the flumazenil is at least about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% pure.
  • the flumazenil is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.8%, or about 99.9% pure.
  • the flumazenil comprises less than about 5%, about 4%, about 3%, about 2%, or about 1% impurities.
  • Improvements of physical properties include, for example, methods of increasing water solubility, bioavailability, serum half-life, and/or therapeutic half-life; and/or modulating biological activity. Modifications known in the art include pegylation, Fc-fusion and albumin fusion. Although generally associated with large molecule agents (e.g., polypeptides), such modifications have recently been evaluated with particular small molecules. By way of example, Chiang, M. et al. (J. Am. Chem.
  • Soc., 2014, 136(9).3370-73) describe a small molecule agonist of the adenosine 2a receptor conjugated to the immunoglobulin Fc domain.
  • the small molecule-Fc conjugate retained potent Fc receptor and adenosine 2a receptor interactions and showed superior properties compared to the unconjugated small molecule.
  • Covalent attachment of PEG molecules to small molecule therapeutics has also been described (Li, W. et al., Progress in Polymer Science, 2013 38.421-44).
  • the GABA receptor modulator of the present disclosure may be administered to a subject in an amount that is dependentupon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof.
  • the dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered. Effective dosage amounts and dosage regimens can readily be determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan.
  • dosing parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the subject (the maximum tolerated dose (MTD) and not less than an amount required to produce a measurable effect on the subject.
  • MTD maximum tolerated dose
  • Such amounts are determined by, for example, the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into consideration the route of administration and other factors.
  • An effective dose is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it.
  • the “median effective dose” or ED 50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered .
  • the ED 50 is commonly used as a measure of reasonable expectance of an agent’ s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors.
  • the effective amount is more than the calculated ED 50
  • the effective amount is less than the calculated ED 50
  • the effective amount is the same as the calculated ED 50 .
  • an effective dose of the GABA receptor modulator may be an amount that, when administered in one or more doses to a subject, produces a desired result relative to a healthy subject.
  • an effective dose may be one that improves a diagnostic parameter, measure, marker and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measure, marker and the like exhibited by a normal subject.
  • the dosage of the compound is contained in a “unit dosage form.”
  • unit dosage form refers to physically discrete units, each unit including a predetermined amount of the compound (e.g., flumazenil, or a hydrate, solvate, or pharmaceutically acceptable salt thereof), sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.
  • Oily suspensions may be formulatedby suspendingthe active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • Dispersible powders and granules suitable for preparation of an aqueous suspensionby the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, and optionally one or more suspending agents and/or preservatives.
  • a dispersing or wetting agent and optionally one or more suspending agents and/or preservatives.
  • suspending agents are exemplified herein.
  • Depot injections which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compound (e.g., GABA receptor modulator (e.g., flumazenil)) disclosed herein over a defined period of time.
  • GABA receptor modulator e.g., flumazenil
  • Depot injections are usually either solid- or oilbased and generally comprise at least one of the formulation components set forth herein .
  • One of ordinary skill in the art is familiar with possible formulations and uses of depot injections .
  • Some formulations include one or more stabilization agents.
  • Potential stabilization agents that are contemplated include buffers. Acetate, Citrate, Sodium Citrate, Tartrate, Phosphate, histidine, bicarbonate, Triethanolamine (TRIS) and their salts.
  • the potential stabilization agents might include antioxidants and preservatives such as. Ascorbic acid, Acetylcysteine (NAC), Sulfurous acid salts (bisulfite, metabisulfite), Monothioglyercol .
  • Butylated hydroxyanisole BHA
  • Butylated hydroxytoluene BHT
  • Tert-butylhydroquinone TBHQ
  • 2’,4’,5’-Trihydroxybutyrophenone phenylhydrazone THBP
  • Ethylenediaminetetraacetic acid EDTA
  • EDTA Ethylenediaminetetraacetic acid
  • SSS Sodium formaldehyde sulfoxylate
  • Tocopherol Vitamin E
  • Ascorbyl palmitate Gallates (e.g., propyl gallate, octyl gallate, lauryl gallate), Cysteine ethyl ether, Tartaric acid, Phosphoric acid, Thiourea, Sodium thioglycolate, Nitrogen, and/or Argon.
  • the potential stabilization agents might include bulking agents, cryoprotectants, and lyoprotectants. Agents that were considered include. Mannitol, Glycine, Sucrose, Lactose, Trehalose, Dextran, Povidone, Sorbitol and/or Poly dextrose. In some formulations potential stabilization agents might include tonicity -adjusting agents. Agents that were considered include, sodium chloride, Glycerin, Mannitol, Dextrose, and/or glycerol. In some formulations the potential stabilization agents might include antimicrobial agents including, but not limited to.
  • soothing agents might include topical analgesics such as. lidocaine, benzocaine, tetracaine, bupivicaine, ropivacaine, and/or levobupivacaine .
  • emulsion stabilizers include hydroxyethyl cellulose, hydroxypropylcellulose, and/or hydroxypropyl methyl cellulose (hypromellose).
  • the compound e.g., GABA receptor modulator (e.g., flumazenil)
  • GABA receptor modulator e.g., flumazenil
  • contemplated by the present disclosure may be in the form of any other suitable pharmaceutical composition currently known or developed in the future.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of flumazenil.
  • the flumazenil may be administered as any of the pharmaceutical compositions provided herein.
  • the flumazenil is administered by subcutaneous injection in an amount of at least 0.5 mg/day from a single device for a period of time of at least 2 days, wherein the single device has a reservoir volume of less than 30 mL.
  • Also provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical compound, wherein the pharmaceutical compound is a GABAA receptor antagonist or modulator, a GABA receptor agonist, a GABA receptor partial agonist, a GABAA receptor negative allosteric modulator or inverse agonist, or salvinorin A, wherein the flumazenil is administered by subcutaneous injection from a single device for a period of time of at least 2 days, wherein the single device has a reservoir volume less than 30 mL.
  • the pharmaceutical compound is a GABAA receptor antagonist or modulator, a GABA receptor agonist, a GABA receptor partial agonist, a GABAA receptor negative allosteric modulator or inverse agonist, or salvinorin A
  • the flumazenil is administered by subcutaneous injection from a single device for a period of time of at least 2 days, wherein the single device has a reservoir volume less than
  • the disease or disorder is benzodiazepine dependence, withdrawal or toxicity.
  • the disease or disorder is benzodiazepine withdrawal.
  • the benzodiazepine withdrawal is acute or post-acute withdrawal, or a combination thereof.
  • the benzodiazepine withdrawal is acute withdrawal.
  • the benzodiazepine withdrawal is post-acute withdrawal.
  • the benzodiazepine withdrawal is both acute and post-acute withdrawal.
  • the disease or disorder is alcohol dependence, withdrawal, or toxicity, sedative dependence, withdrawal, or toxicity, hypnotic dependence, withdrawal, or toxicity, anxiolytic dependence, withdrawal, or toxicity, panic disorder, generalized anxiety disorder, post-traumatic stress disorder (PTSD), idiopathic hypersomnia, narcolepsy, mood disorders, major depression, dysthymia, chronic suicidality, anxiety disorder NOS, obsessive compulsive disorder, eating disorder NOS, anorexia nervosa, bulimia nervosa, intermittent explosive disorder, a sleep disorder, insomnia NOS, a pain disorder, or a chronic pain disorder.
  • PTSD post-traumatic stress disorder
  • idiopathic hypersomnia narcolepsy
  • mood disorders major depression
  • dysthymia chronic suicidality
  • anxiety disorder NOS obsessive compulsive disorder
  • eating disorder NOS anorexia nervosa
  • the single device is adapted to administer the flumazenil or other pharmaceutical compound to the subject over a period of time.
  • Such administration canbe a continuous dose (e.g. at a constant rate) or can be administered according to a pre -determined schedule (e.g. bolus additions of the pharmaceutical composition over a set schedule over the period of time).
  • the period of time is at least about 2 days. In some embodiments, the period of time is about 2 days. In some embodiments, the period of time is about 3 days. In some embodiments, the period of time is about 36 hours to about 72 hours.
  • the period of time is about 36 hours to about 42 hours, about 36 hours to about48 hours, about 36 hours to about 54 hours, about 36 hours to about 60 hours, about 36 hours to about 66 hours, about 36 hours to about 72 hours, about 42 hours to about 48 hours, about 42 hours to about 54 hours, about 42 hours to about 60 hours, about 42 hours to about 66 hours, about 42 hours to about 72 hours, about 48 hours to about 54 hours, about 48 hours to about 60 hours, about 48 hours to about 66 hours, about 48 hours to about 72 hours, about 54 hours to about 60 hours, about 54 hours to about 66 hours, about 54 hours to about 72 hours, about 60 hours to about 66 hours, about 60 hours to about 72 hours, or about 66 hours to about 72 hours.
  • the period of time is about 36 hours, about 42 hours, about 48 hours, about 54 hours, about 60 hours, about 66 hours, or about 72 hours. In some embodiments, the period of time is at least about 36 hours, about 42 hours, about 48 hours, about 54 hours, about 60 hours, or about 66 hours. In some embodiments, the period of time is at most about 42 hours, about 48 hours, about 54 hours, about 60 hours, about 66 hours, or about 72 hours .
  • the single device is adapted to deliver a daily dose of at least 0.5 mg of flumazenil.
  • the pharmaceutical composition is adapted to deliver a daily dose of at least 1 mg of flumazenil.
  • the single device is adapted to deliver a daily dose of at least 1.5 mg of flumazenil.
  • the single device is adapted to deliver a daily dose of at least 2.0 mg of flumazenil.
  • the single device is adapted to deliver a daily dose of at least 2.5 mg of flumazenil.
  • the single device is adapted to deliver a daily dose of at least 3.0 mg of flumazenil.
  • the single device is adapted to deliver a daily dose of flumazenil of about 0.5 mg to about 4 mg. In some embodiments, the single device is adapted to deliver a daily dose of flumazenil of about 0.5 mgto about 1 mg, about 0.5 mgto about 1.5 mg, about 0.5 mgto about
  • the single device is adapted to deliver a daily dose of flumazenil of about 0.5 mg, about 1 mg, about 1.5 mg, about2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, or about4 mg. In some embodiments, single device is adapted to deliver a daily dose of flumazenil of at least about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about2.5 mg, about 3 mg, or about 3.5 mg.
  • the single device is adapted to deliver a daily dose of flumazenil of at most about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, or about 4 mg.
  • the pharmaceutical composition is adapted to deliver a daily dose of flumazenil of up to about 10 mg.
  • the flumazenil is administered in an amount of at least 0.5 mg/day, at least 1.0 mg/day, at least 1.5 mg/day, at least 2 mg/day, at least 3 mg/day, at least 4 mg/day, at least 5 mg/day, at least 7.5 mg/day, or at least 10 mg/day.
  • the pharmaceutical composition is adapted to be administered to be delivered by a wearable device, such as a small pump.
  • a wearable device should have a sufficiently small footprint to allow the wearer to carry on their daily life with minimal disruption. Thus, the maximum volume of such a device should be kept to a minimum.
  • the wearable mini-pump is a 2-day pump.
  • the wearable mini-pump is a 3-day pump.
  • a single wearable mini-pump is used.
  • the single device has a reservoir volume of about 2 mL to about 25 mL.
  • the single device has a reservoir volume of about 2 mL to about 3 mL, about 2 mL to about 5 mL, about 2 mL to about 7.5 mL, about 2 mLto about 10 mL, about 2 mLto about 12.5 mL, about 2 mLto about 15 mL, about 2 mL to about 20 mL, about 2 mL to about 25 mL, about 3 mL to about 5 mL, about 3 mLto about 7.5 mL, about 3 mLto about 10 mL, about 3 mLto about 12.5 mL, about 3 mLto about 15 mL, about 3 mLto about 20 mL, about 3 mLto about 25 mL.
  • the single device has a reservoir volume of at most about 3 mL, about 5 mL, about7.5 mL, about 10 mL, about 12.5 mL, about 15 mL, about20 mL, or about25 mL. In some embodiments, the reservoir volume is less than 20 mL. in some embodiments, the reservoir volume is less than 15 mL. In some embodiments, the reservoir volume is less than 10 mL. In some embodiments, the reservoir volume is less than 5 mL. In some embodiments, the reservoir volume is less than 4 mL. In some embodiments, the reservoir volume is less than 3.5 mL. In some embodiments, the reservoir volume is less than 3 mL. In some embodiments, the reservoir volume as listed above reflects the maximum volume of the reservoir of the single device.
  • the flumazenil is administered as a pharmaceutical composition having a concentration of flumazenil of greater than 0.7 mg/mL. In some embodiments, the concentration of flumazenil is about 0.8 mg/mL to about 10 mg/mL.
  • the concentration of flumazenil is about 0.8 mg/mL to about 1 mg/mL, about 0.8 mg/mL to about 1.2 mg/mL, about 0.8 mg/mL to about 1.5 mg/mL, about 0.8 mg/mL to about 1.8 mg/mL, about 0.8 mg/mL to about 2 mg/mL, about 0.8 mg/mL to about 2.5 mg/mL, about 0.8 mg/mL to about 3 mg/mL, about0.8 mg/mL to about4 mg/mL, about0.8 mg/mL to about 5 mg/mL, about0.8 mg/mL to about 7.5 mg/mL, about 0.8 mg/mL to about 10 mg/mL, about 1 mg/mL to about 1.2 mg/mL, about 1 mg/mL to about 1.5 mg/mL, about 1 mg/mL to about 1.8 mg/mL, about 1 mg/mL to about 2 mg/mL, about 1 mg/mL to about 2.5 mg/mL, about 1 mg/m/mL,
  • the concentration of flumazenil is about 0.8 mg/mL, about 1 mg/mL, about 1.2 mg/mL, about 1.5 mg/mL, about 1.8 mg/mL, about 2 mg/mL, about2.5 mg/mL, about 3 mg/mL, about4 mg/mL, about 5 mg/mL, about 7.5 mg/mL, or about 10 mg/mL.
  • the concentration of flumazenil is at least about 0.8 mg/mL, about 1 mg/mL, about 1 .2 mg/mL, about 1.5 mg/mL, about 1.8 mg/mL, about 2 mg/mL, about2.5 mg/mL, about 3 mg/mL, about4 mg/mL, about 5 mg/mL, or about 7.5 mg/mL.
  • the concentration of flumazenil is at most about 1 mg/mL, about 1 .2 mg/mL, about 1.5 mg/mL, about 1.8 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 7.5 mg/mL, or about 10 mg/mL.
  • the flumazenil or other pharmaceutical compound is administered at a specified rate. Such rate can be continuous, or can be the rate of a particular bolus injection of the compound. In some embodiments, the rate is an average rate over a 24 hour period. In some embodiments, the flumazenil is administered at a rate of about 40 ug/hr to about 250 pg/hr.
  • the flumazenil is administered at a rate of about 40 pg/hrto about 60 pg/hr, about 40 pg/hr/hrto about 80 pg/hr, about 40 pg/hrto about 100 pg/hr, about 40 pg/hr to about 150 pg/hr, about 40 pg/hrto about 200 pg/hr, about 40 pg/hrto about 250 pg/hr, about 60 pg/hr to about 80 pg/hr, about 60 pg/hr to about 100 pg/hr, about 60 pg/hr to about 150 pg/hr, about 60 pg/hrto about 200 pg/hr, about 60 pg/hrto about250 pg/hr, about 80 pg/hr to about 100 pg/hr, about 80 pg/hrto about 150 pg/hr, about 80 pg
  • the flumazenil is administered at a rate of about pg/hr, about 60 pg/hr, about 80 pg/hr, about 100 pg/hr, about 150 pg/hr, about 200 pg/hr, or about 250 pg/hr. In some embodiments, the flumazenil is administered at a rate of at least about 40 pg/hr, about 60 pg/hr, about 80 pg/hr, about 100 pg/hr, about 150 pg/hr, or about 200 pg/hr.
  • the flumazenil is administered at a rate of at most about 60 pg/hr, about 80 pg/hr, about 100 pg/hr, about 150 pg/hr, about 200 pg/hr, or about 250 pg/hr.
  • the pharmaceutical compound is administered at a rate of about 40 pg/hrto about 250 pg/hr. In some embodiments, the pharmaceutical compound is administered ata rate of about 40 pg/hrto about 60 pg/hr, about 40 pg/hrto about 80 pg/hr, about 40 pg/hrto about 100 pg/hr, about 40 pg/hrto about 150 pg/hr, about 40 pg/hrto about 200 pg/hr, about 40 pg/hr, to about 250 pg/hr, about 60 pg/hrto about 80 pg/hr, about 60 pg/hr to about 100 pg/hr, about 60 pg/hrto about 150 pg/hr, about 60 pg/hrto about200 pg/hr, about 60 pg/hrto about250 pg/hr, about 80 pg/
  • the pharmaceutical compound is administered at a rate of about 40 pg/hr, about 60 pg/hr, about 80 pg/hr, about 100 pg/hr, about 150 pg/hr, about 200 pg/hr, or about 250 pg/hr. In some embodiments, the pharmaceutical compound is administered at a rate of atleast about40 pg/hr, about 60 pg/hr, about 80 pg/hr, about 100 pg/hr, about 150 pg/hr, or about 200 pg/hr.
  • the pharmaceutical compound is administered at a rate of at most about 60 pg/hr, about 80 pg/hr, about 100 pg/hr, about 150 pg/hr, about 200 pg/hr, or about 250 pg/hr.
  • the rate of administration may vary over the course of the dosage regimen. For example, an initial rate of administration may be slower during a treatment for benzodiazepine withdrawal when the subject is undergoing a benzodiazepine taper.
  • the rate of administration may lower at the end of the regimen in order to curtail any potential side effects or withdrawal symptoms from administration of the pharmaceutical compound (e.g. flumazenil) itself.
  • the pharmaceutical compound e.g. flumazenil
  • a subject is administered the course of the therapy by using several devices comprising a reservoir of flumazenil or other pharmaceutical compound in a sequential manner.
  • the method further comprises administering to the subject a therapeutically effective amount of flumazenil or other pharmaceutical compound from one or more additional single devices, wherein each additional single device is administered to the subject after an additional iteration of the period of time.
  • the course of treatment requires administration of flumazenil or other pharmaceutical compound from at least 2, at least 3, at least 4, at least 5, at least 6, at least ?, at least 8, at least 9, or at least 10 or more devices.
  • Each device may be used for the same or a different amount of time depending on the duration and course of the therapy.
  • the concentration of API in each device and the rate of administration may also be the same or varied across devices.
  • the total time of administration (e.g., administration across multiple devices) is at least 5 days, at least 10 days, at least 15 days, at least 20 days, at least 25 days, or at least 30 days. In some embodiments, the total time of administration is about 5 days to about 30 days.
  • the total time of administration is about 5 days to about 10 days, about 5 days to about 15 days, about 5 days to about 20 days, about 5 days to about 25 days, about 5 days to about 30 days, about 10 days to about 15 days, about 10 days to about 20 days, about 10 days to about25 days, about 10 days to about 30 days, about 15 days to about20 days, about 15 days to about 25 days, about 15 days to about 30 days, about 20 days to about 25 days, about 20 days to about 30 days, or about 25 days to about 30 days. In some embodiments, the total time of administration is about 5 days, about 10 days, about 15 days, about 20 days, about 25 days, or about 30 days.
  • the total time of administration is at least about 5 days, about 10 days, about 15 days, about 20 days, or about 25 days. In some embodiments, the total time of administration is at most about 10 days, about 15 days, about 20 days, about 25 days, or about 30 days. In some embodiments, the total time of administration is about 5 days to about 90 days.
  • the total time of administration is about 5 days to about 15 days, about 5 days to about 30 days, about 5 days to about 45 days, about 5 days to about 60 days, about 5 days to about 75 days, about 5 days to about 90 days, about 15 days to about 30 days, about 15 days to about 45 days, about 15 days to about 60 days, about 15 days to about 75 days, about 15 days to about 90 days, about 30 days to about45 days, about 30 days to about 60 days, about 30 days to about 75 days, about 30 days to about 90 days, about 45 days to about 60 days, about 45 days to about 75 days, about 45 days to about 90 days, about 60 days to about 75 days, about 60 days to about 90 days, or about 75 daysto about 90 days.
  • the total time of administration is about 5 days, about 15 days, about 30 days, about 45 days, about 60 days, about 75 days, or about 90 days. In some emb odiments, the total time of administration is at least about 5 days, about 15 days, about 30 days, about 45 days, about 60 days, or about 75 days. In some embodiments, the total time of administration is at most about 15 days, about 30 days, about 45 days, about 60 days, about 75 days, or about 90 days.
  • the pharmaceutical compound is a compound that modulates one or more GABA receptors, such as the GABAA receptor.
  • the pharmaceutical compound is a GABA A receptor antagonist or modulator, a GABA receptor agonist, a GABA receptor partial agonist, a GABA A receptor negative allosteric modulator or inverse agonist, or salvinorin A, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the GABA A receptor antagonist or modulator is flumazenil or pentylenetetrazol.
  • the GABA receptor agonist is muscimol, thiomuscimol, or gaboxadol.
  • the GAB A receptor partial agonist is bretazenil, imidazenil, FG 8205 (7-chloro-5-methyl-3-(5-propan-2-yl-l,2,4-oxadiazol- 3-yl)-4H-imidazo[l,5-a][l,4]benzodiazepin-6-one), abecarnil, NS 2710 (l -[l-[3-(3- pyridyl)phenyl]benzimidazol-5-yl]ethanone O-ethyloxime), RWJ-51204 (5-ethoxymethyl-7- fluoro-3-oxo-l,2,3,5-tetrahydrobenzo[4,5] imidazo[l,2a]pyridine-4-N-(2- fluorophenyl)carboxamide), or premazepam.
  • the GAB A A receptor negative allosteric modulator or inverse agonist is bemegride, flurothyl, or pentylenetetrazol.
  • the a5 subunit containing GAB A A receptor selective compound is basmisanil, a5IA (3-(5-methylisoxazol-3-yl)-6-[(l-methyl-lH-l,2,3-triazol-4- yl)methoxy][l,2,4]triazolo[3,4-a]phthalazine), L-655,708, MRK-016, PWZ-029, a Pyridazine, Ro4938581, TB-21007, FG-7142 (N-Methyl-9H-pyrido[5,4-b]indole-3-carboxamide), Rol6- 0154 (ethyl 7-iodanyl-5-methyl-6-oxo-4H-imidazo[l,5-a][l
  • the methods provided herein are used to treat benzodiazepine dependence, withdrawal, or toxicity, or any combination thereof.
  • the benzodiazepine dependence, withdrawal, and/or toxicity has resulted from the subject ingesting or being administered adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, bromazolam, brotizolam, camazepam, chlorodiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam, diclaepam, estazolam, ethyl carfluzepate, ethyl loflazepate, flualprazolam, flubromazepam, flubromazolam, flunit
  • the methods provided herein are used to treat alcohol dependence, withdrawal, or toxicity, sedative dependence, withdrawal, or toxicity, hypnotic dependence, withdrawal, or toxicity, anxiolytic dependence, withdrawal, or toxicity, panic disorder, generalized anxiety disorder, post-traumatic stress disorder (PTSD), idiopathic hypersomnia, narcolepsy, a mood disorder, major depression, dysthymia, chronic suicidality, anxiety disorder NOS, obsessive compulsive disorder, eating disorder NOS, anorexia nervosa, bulimia nervosa, intermittent explosive disorder, a sleep disorder, insomnia NOS, a pain disorder, or a chronic pain disorder.
  • PTSD post-traumatic stress disorder
  • idiopathic hypersomnia narcolepsy
  • a mood disorder major depression, dysthymia, chronic suicidality
  • anxiety disorder NOS obsessive compulsive disorder
  • eating disorder NOS anorexia nervosa
  • the methods provided herein are used to treat alcohol dependence, withdrawal, or toxicity.
  • the methods provided herein are used to treat sedative dependence, withdrawal, or toxicity.
  • the methods provided herein are used to treat hypnotic dependence, withdrawal, or toxicity.
  • the methods provided herein are used to treat anxiolytic dependence, withdrawal, or toxicity.
  • the methods provided herein are used to treat panic disorder.
  • the methods provided herein are used to treat generalized anxiety disorder.
  • the methods provided herein are used to treat post-traumatic stress disorder (PTSD).
  • PTSD post-traumatic stress disorder
  • the methods provided herein are used to treat idiopathic hypersomnia.
  • the methods provided herein are used to treat narcolepsy.
  • the methods provided herein are used to treat mood disorders.
  • the methods provided herein are used to treat dysthymia.
  • the methods provided herein are used to treat chronic suicidality.
  • the methods provided herein are used to treat anxiety disorder NOS.
  • the methods provided herein are used to treat obsessive compulsive disorder. [188] In some embodiments, the methods provided herein are used to treat an eating disorder. In some embodiments, the eating disorder is anorexia nervosa, bulimia nervosa, or eating disorderNOS.
  • the methods provided herein are used to treat intermittent explosive disorder.
  • the methods provided herein are used to treat insomnia.
  • the methods provided herein are used to treat pain disorder.
  • the pharmaceutical compound e.g flumazenil
  • an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered subcutaneously by injection (e.g., bolus or infusion) or by a wearable mini-pump.
  • the pharmaceutical compound e.g flumazenil
  • the wearable mini-pump is a 2-day pump.
  • the wearable mini-pump is a 3-day pump.
  • a single wearable mini-pump is used.
  • flumazenil can be useful in the management of withdrawal symptoms following cessation of benzodiazepine use. It has been observed that dosages of ⁇ 1 -2mg of flumazenil administered as a bolus over a period of several hours was able to reduce withdrawal symptoms in high dose benzodiazepine patients who had been abstinent from benzodiazepines for a period of at least three weeks. It has also more recently been determined such bolus administrations in conjunction with benzodiazepine tapering resulting in reduction of benzodiazepine withdrawal symptoms, reduced craving, and increased completion of cessation of benzodiazepines without relapse. Even more recently, it has been observed that continuous dosing at 2 mg/24h over a continuous period of 96h by IV with oxazepam tapering successfully managed to drastically curtail withdrawal symptoms over the dosing period.
  • the comfort of the patient might be reasonably expected to be slowed by the taper of the benzodiazepine or sedative from 5 days to approximately 10 to 90 days in order to decrease the development of post-acute withdrawal symptoms known to be associated with rapid benzodiazepine taper.
  • the taper of the benzodiazepine or sedative from 5 days to approximately 10 to 90 days in order to decrease the development of post-acute withdrawal symptoms known to be associated with rapid benzodiazepine taper.
  • a treatment program or process as described is essentially not possible in the current art due to the costs associated with long hospital stays or at home IV infusions, the substantial dangers of infection associated with long term IV placement, the labs required and dangers associated with longterm high volume IV fluid infusions and the notable production of expensive medical waste requiring special disposal.
  • a subcutaneous formulation that could be administered at home by the patient would offer significant improvements.
  • commercially available preparations are rather acidic, having a pH of -4.0, which would lead to substantial injection site pain if used as is.
  • the formulations provided herein having an elevated concentration of flumazenil (up to -10 mg/mL) at a physiologically tolerable pH (—5-8) and physiologically compatible osmolality (-300 mOsm/kg) offer substantial benefits and wouldbe amenableto subcutaneous administration.
  • Such formulations allow the patient to self-administer the treatment throughout a prescribed regimen, which can last up to -90 days or more in order to treat benzodiazepine withdrawal, while administering from a small device (e.g. a device having a reservoir of ⁇ 3 mL) that has minimal impact on the lifestyle of the user.
  • a small device e.g. a device having a reservoir of ⁇ 3 mL
  • Such a formulation would also reduce injection site pain associated with other formulations at lower pH’s or elevated osmolalities.
  • Another advantage provided by the formulations and methods disclosed herein is administration of one or more doses of a drug such as flumazenil according to a programmed dosage regimen.
  • a drug such as flumazenil
  • Such devices allow drug administration in the traditional hospital or clinic setting, but also provide the option to self -administer at home or outside the hospital/clinic setting.
  • a doctor or healthcare provider can program a delivery device with a dosage regimen, and the patient or subject is able to use the device to self -administer one or more doses at home. The subject is thus given limited control to implementthe pre-programmed dosage regimen.
  • the use of the pre-programmed dosage regimen to self -medicate outside of the clinic allows accurate titration of blood levels with minimally effective doses of an active ingredient such as flumazenil.
  • the dosage regimen can be programmed to control the rate of drug delivery to mitigate certain side effects known to be associated with flumazenil usage.
  • the dosage regimen is programmed for sustained release and/or extended release dosing of a drug such as flumazenil.
  • the formulations and method provided herein allow a medical professional to implement a pre-programmed dose regimen of flumazenil that can be tailored the specific needs of a patient, particularly depending on the manner in which the patient is ceasing use of benzodiazepine or sedative use.
  • a patient undergoing a taper of benzodiazepine may require only a minimal dosage of flumazenil for the first stage of the taper where the dose of benzodiazepine will still be high.
  • less flumazenil or other GABA receptor modulator compound may be required as withdrawal symptoms are likely to be less severe at this stage.
  • the daily dosage of flumazenil can thus be tailored to the taper of the benzodiazepine such that only as much flumazenil as is necessary is administered at a given time, with more flumazenil being administered as the taper continues and the patient receives a lower dose of benzodiazepine. Additionally, the dose of flumazenil itself can be tapered off near the regimen in order to avoid or minimize any effects of potential flumazenil withdrawal. Any such pre-programmed schedule can be accommodated as required by the prescribing medical professional.
  • Flumazenil solubility curves in the presence of a complexing agent possibly to include any of the described agents in this document and/or potentially to include a sulfobutylether-P-cyclodextrin (e.g., Captisol®) or a hydroxypropyl-P-cyclodextrin (e.g., Cavasol®) is predicted to establish the percentage of flumazenil that is successfully held in solution at a given target pH, the achievement of which would be impossible without said complexing agent.
  • a complexing agent possibly to include any of the described agents in this document and/or potentially to include a sulfobutylether-P-cyclodextrin (e.g., Captisol®) or a hydroxypropyl-P-cyclodextrin (e.g., Cavasol®) is predicted to establish the percentage of flumazenil that is successfully held in solution at a given target pH, the achievement of which would be impossible without said complexing agent.
  • Solubilizing agents will be tested to characterize flumazenil solubility curves within different concentrations of solubilizing agents potentially including but not limited to sulfobutyl- ether-beta-cyclodextrin (e.g., Captisol®), hydroxypropyl-beta-cyclodextrin or other cyclodextrin entities will be provided.
  • solubilizing agents potentially including but not limited to sulfobutyl- ether-beta-cyclodextrin (e.g., Captisol®), hydroxypropyl-beta-cyclodextrin or other cyclodextrin entities will be provided
  • Drawbacks include high osmolality at elevated concentration due to presence of sodium ions. However, this drawback can be overcome by preparing a free acid derivative, which canthen form counterions with either a flumazenil itself or b) appropriate buffer added to the formulation.
  • a patient is either diagnosed with benzodiazepine dependence or suffering from benzodiazepine withdrawal.
  • the patient either has stopped administering or ingesting benzodiazepines or is undergoing a tapering down of benzodiazepine regimen.
  • the patient is prescribed a regimen of flumazenil by subcutaneous injection.
  • the regimen is to include 3 mg/day of flumazenil at continuous dosing for a period of30 days, during which the subject will receive a tapering of benzodiazepine or will abstain from taking any benzodiazepine.
  • the prescription includes 10 wearable pump devices configured to deliver the flumazenil formulation provided herein at a continuous rate such that the subject receives the prescribed 3 mg/day of flumazenil.
  • Each wearable pump device contains a 3 mL reservoir of the flumazenil formulation provided herein at a concentration of 3.5 mg/mL flumazenil.
  • the patient applies the wearable pump device to their body and initiates the pump to begin the regimen.
  • the pump operates continuously to administer the required volume to deliver the prescribed 3 mg/day flumazenil.
  • the wearable pump device On the third day, before the wearable pump device has ejected the full volume of the reservoir, the patient removes the first device and applies a second device, then resumes the regimen. The is repeated for each of the 10 devices until the dosing regimen is completed.
  • Captisol acid (6.26% moisture, 8.14 mg active, 8.70 mgM.C.) was dissolved in HPLC grade H 2 O in a test tube and stirred vigorously. A total of 8.0 mg of flumazenil was weighed out and added in portions to the Captisol acid solution. The first portion ( ⁇ 2 mg) was added and stirred vigorously. The flumazenil did not immediately dissolve, but went into solution after ⁇ 30 min. A second portion ( ⁇ 2 mg) was then added and stirred, but substantial solids remained insoluble. The mixture was stirred overnight and solid was still suspended in solution the next day.
  • Flumazenil-y-Cy clodextrin complex a solution of y-cyclodextrin (200 mg) was dissolved in HPLC grade H 2 O to make 1 mL of a 20% solution in a volumetric flask. Flumazenil (1 .1 mg) was then added and stirred. While initially the flumazenil dissolved to give a transparent solution, the solution became cloudy overtime. Sonication and vigorous stirring did not cause the precipitate to dissolve. This prompted the investigation of saturating y-cyclodextrin solution with flumazenil.
  • flumazenil 49 mg, 50.1 mg total was added to the cloudy solution and the mixture was stirred with a magnetic Teflon stirbar for 48 h at room temperature. The suspension was filtered through a 0.45 pm syringe filter and diluted in duplicate to determine the concentration of flumazenil by HPLC. [Flumazenil]: 2.41 mg/mL.
  • hydroxypropyl-P-cyclodextrin 800 mg was dissolved in HPLC grade H 2 O in a volumetric flask to make 2 mL of a 40% solution.
  • Flumazenil 50 mg
  • a magnetic Teflon stirbar were added and the test tube sealed with parafilm, covered in aluminum foil, and allowed to stir for 48 h at room temperature.
  • the mixture was then filtered through a 0.45 pm syringe filter and osmolality measured.
  • the sample was also diluted in duplicate to determine the concentration of flumazenil by HPLC. Osmolality: 652 mOsm/kg [Flumazenil]: 3.8 mg/mL.
  • Captisol-Ethylenediamine-Flumazenil complex solution without pH adjustment
  • Captisol-ethylenediamine (40% Captisol acid equivalent) was prepared by titrating a solution of Captisol acid in HPLC grade H 2 O with ethylenediamine (0.5 molar equivalent). Specifically, Captisol acid (6.41% moisture, 2.0 g active, 2.14 g M.C.) was dissolved in HPLC grade H 2 O (3.5 mL) and ethylene diamine (215 pL, 193 mg) was added in 5 portions via micropipette. The solution was allowed to stir for ⁇ 2 min between aliquot additions.
  • the solution was diluted with HPLC grade H 2 O to a final volume of 5 mL in a volumetric flask.
  • the solution was diluted to 30% Captisol (acid equivalents) in a test tube and flumazenil (7.5 mg) was added to make a target concentration of 1.5 mg/mL.
  • the transparent, yellow solution was sealed with parafilm, covered in aluminum foil, and stirred for 48 h at it The solution was filtered through a 0.45 pm syringe filter and osmolality measured.
  • the sample was also diluted in duplicate to determine the concentration of flumazenil by HPLC and this was repeated three times.
  • the sample was stored in a parafilm sealed 20 mL glass scintillation vial and covered in aluminum foil to protect from light. Final pH: 6.41.
  • Osmolality 702 mOsm/kg [Flumazenil]: 1.15 ⁇ 0.05 mg/mL.
  • Captisol acid (8.81% moisture, 1.50 g active, 1.64 gM.C.) was dissolved in HPLC grade H 2 O (3 mL) in a test tube with a magnetic Teflon stirbar and stirred vigorously via magnetic stirring.
  • Ethylenediamine (161 pL, 144.9 mg) was added in a single portion with stirring followed by adding benzethonium chloride (50 pL of 1% solution, final concentration 0.01%). The solution was then titrated with 2M HC1 (90 pL total) until a final pH of 4.99.
  • the solution was diluted to a final volume of 5 mL in a volumetric flask and then flumazenil (7.6 mg) was added directly to the volumetric flask.
  • the mixture was sealed with parafilm, covered in aluminum foil, and allowed to stand at room temperature for 48 h with periodic agitation.
  • the mixture was filtered through a 0.45 pm syringe filter and osmolality was measured.
  • the sample was also diluted in duplicate to determine the concentration of flumazenil by HPLC and repeated three times.
  • the solution was stored in a parafilm sealed scintillation vial and covered in aluminum foil to protect from light. Osmolality: 875.3 mOsm/kg. [Flumazenil]: 1.35 ⁇ 0.07 mg/mL. Final pH: 4.99.

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Abstract

Sont fournis dans la description, des formulations sous-cutanées de flumazénil qui sont utiles pour traiter une variété de maladies et de troubles. Les formulations sous-cutanées de flumazénil de la présente invention réduisent l'irritation du site d'injection et la douleur et permettent une administration à domicile afin d'améliorer l'observance du patient.
EP21895529.2A 2020-11-18 2021-11-17 Formulations de flumazénil pour injection sous-cutanée et méthodes de traitement utilisant des modulateurs du récepteur gaba Pending EP4247386A1 (fr)

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JP2014511382A (ja) * 2011-02-23 2014-05-15 コエルルウス リミテッド フルマゼニル錯体、それを含む組成物、およびその使用
CA2876012A1 (fr) * 2012-06-21 2013-12-27 Ucb Pharma S.A. Preparation pharmaceutique
CN111330019B (zh) * 2018-12-18 2022-03-15 中国人民解放军第二军医大学 氟马西尼包合物及其制备方法和应用

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